Aminoheterocyclic derivatives as antithrombotic or anticoagulant

ABSTRACT

The invention concerns compounds of formula (I), wherein each of G 1 , G 2  and G 6  is CH or n; m is 1 or 2; R 1  includes hydrogen, halogeno and (1-4C)alkyl; M 1  is a group of formula: NR 2  -L 1  -T 1  R 3 , in which R 2  and R 3  together form a (1-4C)alkylene group, L 1  includes (1-4C)alkylene, and T 1  is CH or N; A may be a direct link; M 2  is a group of the formula: (T 2  R 4 ) r  -L 2  T 3  R 5  in which R is 0 or 1, each of T 2  and T 3  is CH or N, each of R 4  and R 5  is hydrogen or (1-4C)alkyl, or R 4  and R 5  together form a (1-4C)alkylene group, and L 2  includes (1-4C)alkylene; M 3  may be a direct link to X; X includes sulphonyl; and Q includes naphthyl and a heterocycle moiety; or a pharmaceutically-acceptable salt thereof; processes for their preparation, pharmaceutical compositions containing them and their use as antithrombotic or anticoagulant agents.

This application is a 371 of PCT/GB95/02285 filed Sep. 25, 1995.

The invention relates to a group of aminoheterocyclic derivatives, orpharmaceutically-acceptable salts thereof, which possess antithromboticand anticoagulant properties and are accordingly useful in methods oftreatment of the human or animal body. The invention also relates toprocesses for the preparation of said aminoheterocyclic derivatives, topharmaceutical compositions containing them and to their use in themanufacture of medicaments for use in the production of anantithrombotic or anticoagulant effect.

The antithrombotic and anticoagulant effect produced by the compounds ofthe invention is believed to be attributable to their strong inhibitoryeffect against the activated coagulation protease known as Factor Xa.Factor Xa is one of a cascade of proteases involved in the complexprocess of blood coagulation. The protease known as thrombin is thefinal protease in the cascade and Factor Xa is the preceding proteasewhich cleaves prothrombin to generate thrombin.

Certain compounds are known to possess Factor Xa inhibitory propertiesand the field has been reviewed by R. B. Vallis, Current Opinion inTherapeutic Patents, 1993, 1173-1179. Thus it is known that twoproteins, one known as antistatin and the other known as tickanticoagulant protein (TAP), are specific Factor Xa inhibitors whichpossess antithrombotic properties in various animal models of thromboticdisease.

It is also known that certain non-peptidic compounds possess Factor Xainhibitory properties. Of the low molecular weight inhibitors mentionedin the review by R. B. Wallis, all possessed a strongly basic group suchas an amidinophenyl or amidinonaphthyl group.

It is the object of the present invention to provide a new class ofagent which lacks the amidino group previously believed to be anessential feature for a Factor Xa inhibitor.

We have now found that certain amino-substituted heterocyclicderivatives possess Factor Xa inhibitory activity. Many of the compoundsof the present invention also possess the advantage of being selectiveFactor Xa inhibitors, that is the enzyme Factor Xa is inhibited stronglyat concentrations of test compound which do not inhibit or which inhibitto a lesser extent the enzyme thrombin which is also a member of theblood coagulation enzymatic cascade.

The compounds of the present invention possess activity in the treatmentor prevention of a variety of medical disorders where anticoagulanttherapy is indicated, for example in the treatment or prevention ofthrombotic conditions such as coronary artery and cerebro-vasculardisease. Further examples of such medical disorders include variouscardiovascular and cerebrovascular conditions such as myocardialinfarction, the formation of atherosclerotic plaques, venous or arterialthrombosis, coagulation syndromes, vascular injury including reocclusionand restenosis following angioplasty and coronary artery bypass surgery,thrombus formation after the application of blood vessel operativetechniques, the introduction of artificial heart valves or on therecirculation of blood, cerebral infarction, cerebral thrombosis,stroke, cerebral embolism, pulmonary embolism, ischaemia and angina(including unstable angina).

The compounds of the invention are also useful as inhibitors of bloodcoagulation in an ex-vivo situation such as, for example, the storage ofwhole blood or other biological samples suspected to contain Factor Xaand in which coagulation is detrimental.

According to one aspect of the invention there is provided anaminoheterocyclic derivative of the formula I (set out hereinafter)wherein G¹ is CH or N;

G² is CH or N;

G³ is CH or N;

m is 1 or 2;

R¹ is hydrogen, amino, halogeno, cyano, (1-4C) alkyl or (1-4C) alkoxy;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form a (1-4C) alkylene group,

L¹ is (1-4C)alkylene,

and

T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the ring formed whenR² and R³ are linked optionally bears a (1-4C)alkyl substituent;

A is a direct link to the carbonyl group, or A is (1-4C) alkylene;

M² is a group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 0 or 1,

T² is CH or N,

T³ is CH or N,

R⁴ is hydrogen or (1-4C) alkyl, R⁵ is hydrogen or (1-4C) alkyl, or R⁴and

R⁵ together form a (1-4C) alkylene, methylenecarbonyl orcarbonylmethylene group, or R⁴ is a (2-3C) alkylene group which islinked to a methylene group within L² forming a 5- or 6-membered ringinvolving R⁴ and T², or

R⁵ is a (2-3C)alkylene group which is linked to a methylene group withinL² forming a 5- or 6-membered ring involving R⁵ and T³,

L² is (1-4C) alkylene, (3-6C)cycloalkane-1,2-diyl, (1-3C)alkylene-carbonyl or phenylene, and, when r is 1, L² may also becarbonyl-(1-3C)alkylene, and wherein 1 or 2 methylene groups within L²and the rings formed when R⁴ and R⁵, R⁴ and L² or R⁵ and L² are linkedoptionally bears a substituent selected from the group consisting ofoxo, carboxy, (1-4C) alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoylN-(1-4C)alkyl-N-phenylcarbamoyl, N-[phenyl-(1-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]carbamoyl,N-[hydroxy-(2-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[hydroxy-(2-3C)alkyl]carbamoyl,N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl,N-[carboxy-(1-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[carboxy-(1-3C)alkyl]carbamoyl,N-[carboxy-(1-3C)alkyl]-N-[hydroxy-(2-3C)alkyl]carbamoyl,N-[carboxy-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl,N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl,N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[hydroxy-(2-3C)alkyl]carbamoyl,N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl,(1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl,carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl,pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl,morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl,N-phenylcarbamoyl-(1-4C)alkyl,N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl,(1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl, and wherein anyheterocyclic group in said substituent optionally bears 1 or 2substituents selected from the group consisting of (1-4C)alkyl,(1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl, and wherein anyphenyl or phenylene group in M² optionally bears 1 or 2 substituentsselected from the group consisting of halogeno, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 0 or 1,

R⁶ is hydrogen or (1-4C)alkyl, or R⁵ and R⁶ together form a(1-4C)alkylene, methylenecarbonyl or carbonylmethylene group, or R6 is a(2-3C)alkylene group which is linked to a methylene group within L³forming a 5- or 6-membered ring involving NR⁶, L³ is (1-4C)alkylene,(3-6C)cycloalkane-1,2-diyl, carbonyl-(1-3C)alkylene or phenylene, and,when s is 1, L³ may also be (1-3C)alkylene-carbonyl,

and wherein 1 or 2 methylene groups within L³ and the rings formed whenR⁵ and R⁶ or R6 and L3 are linked optionally bears a substituentselected from the group consisting of oxo, carboxy,(1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl,N-(1-4C)alkyl-N-phenylcarbamoyl, N-[phenyl-(1-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]carbamoyl, (1-4C)alkyl,carboxy-(1-4C)alkyl,, (1-4C)alkoxycarbonyl-(1-4C)alkyl,carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl,pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl,morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl,N-phenylcarbamoyl-(1-4C)alkyl,N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl,(1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl,

and wherein any heterocyclic group in said substituent optionally bears1 or 2 substituents selected from the group consisting of (1-4C)alkyl,(1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl, and wherein anyphenyl or phenylene group in H³ optionally bears 1 or 2 substituentsselected from the group consisting of halogeno, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy;

X is oxy, thio, sulphinyl, sulphonyl, carbonyl, carbonyloxy,carbonylamino, N-(1-4C)alkylcarbonylamino, sulphonylamino, methylene,(1-4C)alkylmethylene or di-(1-4C)alkylmethylene, or, when T³ is CH andM³ is a direct link to X, X may also be aminosulphonyl or oxycarbonyl;

and

Q is phenyl, naphthyl, phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl,phenyl-(2-4C)alkynyl, (5-7C)cycloalkyl or a heterocyclic moietycontaining up to 4 heteroatoms selected from the group consisting ofnitrogen, oxygen and sulphur, and Q optionally bears 1, 2 or 3substituents selected from the group consisting of hydroxy, amino,halogeno, cyano, trifluoromethyl, nitro, carboxy, carbamoyl, formyl,formimidoyl, formohydroximoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl,(1-4C)alkylamino, di-(1-4C)alkylamino, (2-4C)alkanoylamino,(2-4C)alkanoyl, (2-4C)alkanoimidoyl, (2-4C)alkanohydroximoyl, phenyl,heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl,heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl,benzyl and benzoyl,

and wherein said heteroaryl substituent or the heteroaryl group in aheteroaryl-containing substituent comprises a 5- or 6-memberedmonocyclic heteroaryl ring containing up to 3 heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulphur, and wherein saidphenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl,phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl,heteroarylsulphonyl, benzyl or benzoyl substituent optionally bears 1,2, 3 or 4 substituents selected from the group consisting of halogeno,trifluoromethyl, cyano, trifluoromethoxy, nitro, (1-4C)alkyl,(1-4C)alkoxy, hydroxy, amino, carboxy, carbamoyl, (1-4C)alkoxycarbonyl,N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, (1-4C)alkylamino,di-(1-4C)alkylamino, (2-4C)alkanoylamino and tetrazolyl;

or a pharmaceutically-acceptable salt thereof.

The chemical formulae referred to herein by Roman numerals are set outfor convenience on a separate sheet hereinafter. In this specificationthe term "alkyl" includes both straight and branched chain alkyl groupsbut references to individual alkyl groups such as "propyl" are specificfor the straight chain version only. An analogous convention applies toother generic terms.

It is to be understood that certain aminoheterocyclic derivatives of thepresent invention can exist in solvate as well as unsolvated forms suchas, for example, hydrated forms. It is to be understood that theinvention encompasses all such solvated forms which possess Factor Xainhibitory activity.

It is further to be understood that, insofar as certain of the compoundsof the formula defined above may exist in optically active or racemicforms by virtue of one or more asymmetric carbon atoms, the inventionencompasses any such optically active or racemic form which possessesFactor Xa inhibitory activity. The synthesis of optically active formsmay be carried out by standard techniques of organic chemistry wellknown in the art, for example by synthesis from optically activestarting materials or by resolution of a racemic form.

According to a further aspect of the invention there is provided anaminoheterocyclic derivative of the formula Ia wherein G¹ is CH or N;

G² is CH or N;

m is 1 or 2;

R¹ is hydrogen, amino, halogeno, cyano, (1-4C)alkyl or (1-4C)alkoxy;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form a (1-4C)alkylene group,

L¹ is (1-4C)alkylene, and

T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the rings formed whenR² and R³ are linked optionally bears a (1-4C)alkyl substituent;(1-4C)alkyl and (1-4C)alkoxy;

A is a direct link to the carbonyl group, or A is (1-4C)alkylene;

M² is a group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 T.sup.3 R.sup.5

in which r is 0 or 1,

T² is CH or N,

T³ is CH or N,

R⁴ is hydrogen or (1-4C)alkyl, R⁵ is hydrogen or (1-4C)alkyl, or R⁴ and

R⁵ together form a (1-4C)alkylene, methylenecarbonyl orcarbonylmethylene group, or R⁴ is a (2-3C)alkylene group which is linkedto a methylene group within L² forming a 5- or 6-membered ring involvingR and T², or R⁵ is a (2-3C)alkylene group which is linked to a methylenegroup within L² forming a 5- or 6-membered ring involving R⁵ and T³,

L² is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl,

(1-3C)alkylene-carbonyl or phenylene, and, when r is 1, L may also becarbonyl-(1-3C)alkylene,

and wherein 1 or 2 methylene groups within L² and the rings formed whenR⁴ and R⁵, R⁴ and L² or R⁵ and L² are linked optionally bears asubstituent selected from the group consisting of carboxy,(1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl,N-(1-4C)alkyl-N-phenylcarbamoyl, N-[phenyl-(1-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]carbamoyl,N-[hydroxy-(2-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[hydroxy-(2-3C)alkyl]carbamoyl,N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl,N-[carboxy-(1-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[carboxy-(1-3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]-N- [hydroxy-(2-3C)alkyl]carbamoyl,N-[carboxy-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl,N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl,N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[hydroxy-(2-3C)alkyl]carbamoyl,N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl,(1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl,carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl,pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl,morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl,N-phenylcarbamoyl-(1-4C)alkyl,N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl,(1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl,

and wherein any heterocyclic group in said substituent optionally bears1 or 2 substituents selected from the group consisting of (1-4C)alkyl,(1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl, and wherein anyphenyl or phenylene group in M2 optionally bears 1 or 2 substituentsselected from the group consisting of halogeno, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 0 or 1,

R⁶ is hydrogen or (1-4C)alkyl, or R⁵ and R⁶ together form a(1-4C)alkylene, methylenecarbonyl or carbonylmethylene group, or R⁶ is a(2-3C)alkylene group which is linked to a methylene group within L³forming a 5- or 6-membered ring involving NR⁶ L³ is (1-4C)alkylene,(3-6C)cycloalkane-1,2-diyl, carbonyl-(1-3C)alkylene or phenylene, and,when s is 1, L³ may also be (1-3C)alkylene-carbonyl,

and wherein 1 or 2 methylene groups within L³ and the rings formed whenR⁵ and R⁶ or R⁶ and L³ are linked optionally bears a substituentselected from the group consisting of carboxy, (1-4C)alkoxycarbonyl,carbamoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl,pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl,N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl,N-[phenyl-(1-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]-carbamoyl, (1-4C)alkyl,carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl,carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl,pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl,morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl,N-phenylcarbamoyl-(1-4C)alkyl,N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl,(1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl,

and wherein any heterocyclic group in said substituent optionally bears1 or 2 substituents selected from the group consisting of (1-4C)alkyl,(1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl,

and wherein any phenyl or phenylene group in M³ optionally bears 1 or 2substituents selected from the group consisting of halogeno,trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;

X is oxy, thio, sulphinyl, sulphonyl, carbonyl, carbonyloxy,carbonylamino, N-(1-4C)alkylcarbonylamino, sulphonylamino, methylene,(1-4C)alkylmethylene or di-(1-4C)alkylmethylene, or, when T is CH and M³is a direct link to X, X may also be aminosulphonyl or oxycarbonyl; and

Q is phenyl, naphthyl, phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl,phenyl-(2-4C)alkynyl, (5-7C)cycloalkyl or a heterocyclic moietycontaining up to 4 heteroatoms selected from the group consisting ofnitrogen, oxygen and sulphur, and Q optionally bears 1, 2 or 3substituents selected from the group consisting of hydroxy, amino,halogeno, cyano, trifluoromethyl, nitro, carboxy, carbamoyl, formyl,formimidoyl, formohydroximoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl,(1-4C)alkylamino, di-(1-4C)alkylamino, (2-4C)alkanoylamino,(2-4C)alkanoyl, (2-4C)alkanoimidoyl, (2-4C)alkanohydroximoyl, phenyl,heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl,heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl,benzyl and benzoyl,

and wherein said heteroaryl substituent or the heteroaryl group in aheteroaryl-containing substituent comprises a 5- or 6-memberedmonocyclic heteroaryl ring containing up to 3 heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulphur,

and wherein said phenyl, heteroaryl, phenoxy, phenylthio,phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio,heteroarylsulphinyl, heteroarylsulphonyl, benzyl or benzoyl substituentoptionally bears 1 or 2 substituents selected from the group consistingof halogeno, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, hydroxy, amino,carboxy, carbamoyl, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, (1-4C)alkylamino, di-(1-4C)alkylamino,(2-4C)alkanoylamino and tetrazolyl;

or a pharmaceutically-acceptable salt thereof.

Suitable values for the generic terms referred to above include thoseset out below.

When m is 2, each R¹ is independently selected from hydrogen, amino,halogeno, cyano, (1-4C)alkyl and (1-4C)alkoxy.

A suitable value for R¹ when it is a halogeno group, for a halogenosubstituent in M² or M³ or for a halogeno substituent in Q is, forexample, fluoro, chloro, bromo or iodo.

A suitable value for R¹ when it is a (1-4C)alkyl group, for a(1-4C)alkyl substituent in M¹, M² or M³ or for a (1-4C)alkyl substituentin Q is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl or tert-butyl.

A suitable value for R¹ when it is a (1-4C)alkoxy group, for a(1-4C)alkoxy -substituent in M² or M³ or for a (1-4C)alkoxy substituentin Q is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy.

A suitable value for R⁴, R⁵ or R⁶ when it is (1-4C)alkyl is, forexample, methyl, ethyl, propyl, isopropyl, butyl or sec-butyl.

A suitable value for a (1-4C)alkylene group formed by R² and R³together, by R⁴ and R⁵ together or by R⁵ and R⁶ together is, forexample, methylene, ethylene, trimethylene or tetramethylene.

A suitable value for a (2-3C)alkylene group by which R⁴ may be linked toa methylene group within L², R⁵ may be linked to a methylene groupwithin L² or R⁶ may be linked to a methylene group within L³ is, forexample, ethylene or trimethylene.

A suitable value for L¹, L² or L³ when it is (1-4C)alkylene is, forexample, methylene, ethylene, trimethylene or tetramethylene; a suitablevalue for L² or L³ when it is (3-6C)cycloalkane-1,2-diyl is, forexample, cyclopropane-1,2-diyl, cyclobutane-1,2-diyl,cyclopentane-1,2-diyl or cyclohexane-1,2-diyl; when it is(1-3C)alkylene-carbonyl is, for example methylenecarbonyl,ethylenecarbonyl or trimethylenecarbonyl; and when it is phenylene is,for example, 1,3- or 1,4-phenylene.

A suitable value for L² and L³ when it is carbonyl-(1-3C)alkylene is,for example, carbonylmethylene, carbonylethylene orcarbonyltrimethylene.

Suitable values for the substituents which may be present within M¹, M²or M³ include, for example:

for (1-4C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl and tert-butoxycarbonyl;

for N-(1-4C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl andN-propylcarbamoyl;

for N,N-di-[(1-4C) alkyl]-carbamoyl: N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl;

for 4-(1-4C)alkylpiperazin-1-ylcarbonyl: 4-methylpiperazin-1-ylcarbonyland 4-ethylpiperazin-1-ylcarbonyl;

for N-(1-4C)alkyl-N-phenylcarbamoyl: N-methyl-N-phenylcarbamoyl andN-ethyl-N-phenylcarbamoyl;

for N-[phenyl-(1-3C)alkyl]-carbamoyl: N-benzylcarbamoyl andN-phenethylcarbamoyl;

for N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]carbamoyl:N-benzyl-N-methylcarbamoyl and N-methyl-N-phenethylcarbamoyl;

for N-[hydroxy-(2-3C)alkyl]-carbamoyl: N-(2-hydroxyethyl)carbamoyl andN-(3-hydroxypropyl)carbamoyl;

for N-(1-4C)alkyl-N-[hydroxy-(2-3C)alkyl]carbamoyl:N-(2-hydroxyethyl)-N-methylcarbamoyl and N-(2-hydroxyethyl)-N-ethylcarbamoyl;

for N-[(1-4C)alkoxy-(2-3C)alkyl]-carbamoyl: N-(2-methoxyethyl)carbamoyland N-(2-ethoxyethyl)carbamoyl;

for N-(1-4C)alkyl-N-[(1-4C)-alkoxy-(2-3C)alkyl]carbamoyl:N-(2-methoxyethyl)-N-methylcarbamoyl andN-(2-ethoxyethyl)-N-ethyl-carbamoyl;

for N-[carboxy-(1-3C)alkyl]-carbamoyl: N-(carboxymethyl)carbamoyl,N-(1-carboxyethyl)carbamoyl and N-(2-carboxyethyl)carbamoyl;

for N-(1-4C)alkyl-N-[carboxy-(1-3C)alkyl]carbamoyl:N-(carboxymethyl)-N-methylcarbamoyl,N-(1-carboxyethyl)-N-methylcarbamoyl andN-(2-carboxyethyl)-N-methylcarbamoyl;

for N-[carboxy-(1-3C)alkyl)]-N-[hydroxy-(2-3C)alkyl]carbamoyl:

N-(carboxymethyl)-N-(2-hydroxyethyl)carbamoyl;

for N-[carboxy-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]-carbamoyl:N-(carboxymethyl)-N-(2-methoxyethyl)carbamoyl;

for N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl:N-(methoxycarbonylmethyl)carbamoyl, N-(ethoxycarbonylmethyl)carbamoyl,N-(1-methoxycarbonylethyl)carbamoyl andN-(2-methoxycarbonylethyl)carbamoyl;

for N-(1-4C)alkyl-N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl:N-(methoxycarbonylmethyl)-N-methylcarbamoyl;

forN-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[hydroxy-(2-3C)alkyl]carbamoyl:N-(2-hydroxyethyl)-N-(methoxycarbonylmethyl)carbamoyl;

forN-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl:N-(methoxycarbonylmethyl)-N-(2-methoxyethyl)carbamoyl;

for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl and butyl;

for carboxy-(1-4C)alkyl: carboxymethyl, 1-carboxyethyl, 2-carboxyethyland 3-carboxypropyl;

for (1-4C)alkoxycarbonyl-(1-4C)alkyl: methoxycarbonylmethyl,ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl,1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl,3-methoxycarbonylpropyl and 3-ethoxycarbonylpropyl;

for carbamoyl-(1-4C)alkyl: carbamoylmethyl, 1-carbamoylethyl,2-carbamoylethyl and 3-carbamoylpropyl;

for N-(1-4C)alkylcarbamoyl-(1-4C)alkyl: N-methylcarbamoylmethyl,N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl,1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl,2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and3-(N-methylcarbamoyl)propyl;

for N,N-di-[(1-4C)alkyl]-carbamoyl-(1-4C)alkyl:N,N-dimethylcarbamoylmethyl, N-ethyl -N-methylcarbamoylmethyl,N,N-diethylcarbamoylmethyl, 1- (N,N-dimethylcarbamoyl)ethyl, 1-(N,N-diethylcarbamoyl)ethyl, 2- (N,N-dimethylcarbamoyl)ethyl, 2-(N,N-diethylcarbamoyl)ethyl and 3-(N,N-dimethylcarbamoyl)propyl;

for pyrrolidin-1-yl-carbonyl-(1-4C)alkyl: pyrrolidin-1-ylcarbonylmethyl,1-(pyrrolidin-1-ylcarbonyl)ethyl and 2-(pyrrolidin-1-ylcarbonyl)ethyl;

for piperidinocarbonyl-(1- 4C)alkyl: piperidinocarbonylmethyl,1-(piperidinocarbonyl) ethyl and 2-(piperidinocarbonyl)ethyl;

for morpholinocarbonyl-(1-4C)alkyl: morpholinocarbonylmethyl,1-(morpholinocarbonyl)ethyl and 2-(morpholinocarbonyl)ethyl;

for piperazin-1-yl-carbonyl-(1-4C)alkyl: piperazin-1-ylcarbonylmethyl,1-(piperazin-1-ylcarbonyl)ethyl and 2-(piperazin-1-ylcarbonyl)ethyl;

for 4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl:4-methylpiperazin-1-ylcarbonylmethyl,4-ethylpiperazin-1-ylcarbonylmethyl,2-(4-methylpiperazin-1-ylcarbonyl)-ethyl and2-(4-ethylpiperazin-1-ylcarbonyl)ethyl;

for N-phenylcarbamoyl-(1-4C)alkyl: N-phenylcarbamoylmethyl and2-(N-phenylcarbamoyl)ethyl;

for N-[phenyl-(1-3C)alkyl]-carbamoyl-(1-4C)alkyl:N-benzylcarbamoylmethyl, N-phenethylcarbamoylmethyl and2-(N-benzylcarbamoyl)ethyl;

for hydroxy-(1-4C)alkyl: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyland 3-hydroxypropyl;

for (1-4C)alkoxy-(1-4C)alkyl: methoxymethyl, ethoxymethyl,1-methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl; and

for phenyl-(1-4C)alkyl: benzyl, phenethyl and 3-phenylpropyl.

Suitable values for substituents which may be present on a heterocyclicgroup within a substituent which may be present within M² or M³ include,for example:

for (1-4C)alkyl: methyl, ethyl, propyl and isopropyl;

for (1-4C)alkoxy: methoxy, ethoxy and propoxy;

for (1-4C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl and tert-butoxycarbonyl;

for N-(1-4C)alkylcarbamoyl: N-methylcarbamoyl and N-ethylcarbamoyl; and

for N,N-di-(1-4C) alkyl-carbamoyl: N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl.

A suitable value for A when it is (1-4C)alkylene is, for example,methylene, ethylene, trimethylene and tetramethylene.

It is to be understood that when M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

the order of the presentation of this group is significant as to theorientation of attachment of the group. Thus it is the NR² group whichis attached to the heterocyclic group, for example, when G¹ and G² areeach CH, the pyridyl group which bears the substituent R¹. It is also tobe understood that within the NR² group it is the N atom which isattached to L¹. Likewise the R² group is attached to the N atom and notto the L¹ group. Similarly in the T¹ R³ group it is the T¹ group whichis attached to the group A of formula I (or the CO group within formulaI when A is a direct link) and the R³ group is attached to the T¹ groupand not to the group A of formula I. A similar convention applies to theattachment of the groups M² and M³ and to the attachment of the T², T³and NR⁶ groups within M² or M³.

It is further to be understood that when R⁴ is a (2-3C)alkylene groupsuch as ethylene and trimethylene which is linked to a methylene groupwhich L² forming a 5- or 6-membered ring involving T² and R⁴, a suitablering so formed when T² is N is, for example, pyrrolidine-1,3-diyl,piperidine-1,3-diyl and piperidine-1,4-diyl and a suitable ring soformed when T² is CH is, for example, cyclopentane-1,3-diyl,cyclohexane-1,3-diyl and cyclohexane-1,4-diyl. Such ring systems arealso suitable when, for example, R⁵ is linked to a methylene groupwithin L². Ring systems such as pyrrolidine-1,3-diyl,piperidine-1,3-diyl and piperidine-1,4-diyl are also suitable when R⁶ islinked to a methylene within L³.

For the avoidance of doubt it is stated that a suitable heterocyclicgroup in a substituent which may be present within M² and M³ includes,for example, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl and4-(1-4C)alkylpiperazin-1-yl whether directly attached or attached by wayof a linking group as in, for example,pyrrolidin-1-ylcarbonyl-(1-4C)alkyl such as2-(pyrrolidin-1-ylcarbonyl)ethyl.

A suitable value for X when it is a N-(1-4C)alkylcarbonylamino group is,for example, N-methylcarbonylamino or N-ethylcarbonylamino; when it is(1-4C)alkylmethylene is, for example, ethane-1,1-diyl orpropane-1,1-diyl; and when it is di-(1-4C)alkylmethylene is, forexample, propane-2,2-diyl. It is also to be understood that when X is acarbonyloxy, carbonylamino or N-(1-4C)alkylcarbonylamino group, it isthe carbonyl group therein which is attached to M³. Likewise when X is asulphonylamino group it is the sulphonyl group therein which is attachedto M³ whereas, when X is an aminosulphonyl group, the sulphonyl grouptherein is attached to Q.

A suitable value for Q when it is naphthyl is, for example, 1-naphthylor 2-naphthyl; when it is phenyl-(1-4C)alkyl is, for example, benzyl,phenethyl and 3-phenylpropyl, when it is phenyl-(2-4C)alkenyl is, forexample, styryl, cinnamyl or 3-phenylprop-2-enyl; when it isphenyl-(2-4C)alkynyl is, for example, 2-phenylethynyl,3-phenylprop-2-ynyl and 3-phenylprop-1-ynyl; and when it is(5-7C)cycloalkyl is, for example, cyclopentyl, cyclohexyl andcycloheptyl.

A suitable value for Q when it is a heterocyclic moiety containing up to4 heteroatoms selected from the group consisting of nitrogen, oxygen andsulphur is, for example, a 5- or 6-membered heterocyclic moiety which isa single ring or is fused to one or two benzo rings such as furyl,benzofuranyl, tetrahydrofuryl, chromanyl, thienyl, benzothienyl,pyridyl, piperidinyl, quinolyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolyl, 1,2,3,4-tetrahydroisoquinolinyl, pyrazinyl, piperazinyl,pyrimidinyl, pyridazinyl, quinoxalinyl, quinazolinyl, cinnolinyl,pyrrolyl, pyrrolidinyl, indolyl, indolinyl, imidazolyl, benzimidazolyl,pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl,benzothiazolyl, isothiazolyl, morpholinyl, 4H-1,4-benzoxazinyl,4H-1,4-benzothiazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,furazanyl, thiadiazolyl, tetrazolyl, dibenzofuranyl and dibenzothienyl,which may be attached through any available position including, for anappropriate X group such as, for example, carbonyl and methylene,through any available nitrogen atom and which may bear up to threesubstituents including a substituent on any available nitrogen atom.

Suitable values for the substituents which may be present within Qinclude, for example:

for (1-4C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl andtert-butoxycarbonyl;

for (1-4C)alkyl: methyl, ethyl, propyl and isopropyl;

for (1-4C)alkoxy: methoxy, ethoxy, propoxy and isopropoxy;

for N-(1-4C)alkylcarbamoyl: N-methylcarbamoyl and N-ethylcarbamoyl;

for N,N-di-(1-4C)alkylcarbamoyl: N,N-dimethylcarbamoyl andN,N-diethylcarbamoyl;

for (1-4C)alkylamino: methylamino, ethylamino and propylamino;

for di-(1-4C)alkylamino: dimethylamino, N-ethyl-N-methylamino anddiethylamino;

for (2-4C)alkanoylamino: acetamido, propionamido and butyramido;

for (2-4C)alkanoyl: acetyl, propionyl and butyryl;

for (2-4C)alkanoimidoyl: acetimidoyl and propionoimidoyl; and

for (2-4C)alkanohydroximoyl: acetohydroximoyl and propionohydroximoyl.

A suitable value for the heteroaryl substituent or the heteroaryl groupin a heteroaryl-containing substituent which comprises a 5- or6-membered monocyclic heteroaryl ring containing up to 3 heteroatomsselected from the group consisting of oxygen, nitrogen and sulphur is,for example, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyland thiadiazolyl which may be attached through any available positionincluding through any available nitrogen atom.

A suitable pharmaceutically-acceptable salt of an aminoheterocyclicderivative of the invention is, for example, an acid-addition salt of anaminoheterocyclic derivative of the invention which is sufficientlybasic, for example, an acid-addition salt with, for example, aninorganic or organic acid, for example hydrochloric, hydrobromic,sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. Inaddition a suitable pharmaceutically-acceptable salt of anaminoheterocyclic derivative of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Particular compounds of the invention include, for example,aminoheterocyclic derivatives of the formula I or of the formula Ia, orpharmaceutically-acceptable salts thereof, wherein, unless otherwisestated, each of G¹, G², G³, m, R¹, M¹, A, M², M³, X and Q has any of themeanings defined hereinbefore or in this section concerning particularcompounds of the invention:

(a) each of G¹, G² and G³ is CH;

(b) each of G¹ and G² is CH and G³ is N, or G¹ is N and each of G² andG³ is CH;

(c) m is 1 and R¹ is hydrogen;

(d) A is a direct link to the carbonyl group;

(e) A is (1-4C)alkylene;

(f) M² is a group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is CH or N, T³ is CH or N,

R⁴ is hydrogen or (l-4C)alkyl, R⁵ is hydrogen or (1-4C)alkyl, or R⁴ andR⁵ together form a (1-4C)alkylene group, or R⁴ is a (2-3C)alkylene groupwhich is linked to a methylene group within L² forming a 5- or6-membered ring involving R⁴ and T², and

L² is (1-4C)alkylene,

and wherein 1 or 2 methylene groups within L² and the rings formed whenR⁴ and R⁵ or R⁴ and L² are linked optionally bears a substituentselected from the group consisting of carboxy, (1-4C)alkoxycarbonyl,carbamoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl,pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl,N-phenylcarbamoyl, (1-4C)alkyl and phenyl-(1-4C)alkyl,

and wherein any heterocyclic group in said substituent optionally bears1 or 2 (1-4C)alkyl substituents,

and wherein any phenyl group in M² optionally bears 1 or 2 substituentsselected from the group consisting of halogeno, (1-4C)alkyl and (1-4C)alkoxy;

(g) M³ is a direct link to X;

(h) M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen or (1-4C)alkyl,

L³ is (1-4C)alkylene or carbonyl-(1-3C)alkylene,

and wherein 1 or 2 methylene groups within L³ optionally bears asubstituent selected from the group consisting of (1-4C)alkyl,hydroxy-(l-4C)alkyl and phenyl-(1-4C)alkyl, and wherein any phenyl groupin M³ optionally bears 1 or 2 substituents selected from the groupconsisting of halogeno, (1-4C)alkyl and (1-4C)alkoxy;

(i) X is thio, sulphinyl or sulphonyl;

(j) X is sulphonyl;

(k) X is carbonyl, carbonyloxy, carbonylamino orN-(1-4C)alkylcarbonylamino;

(l) X is sulphonylamino or, when T³ is CH and M³ is a direct link to X,X may also be aminosulphonyl;

(m) X is methylene, (1-4C)alkylmethylene or di-(1-4C)alkylmethylene;

(n) Q is phenyl, naphthyl or phenyl-(1-4C)alkyl which optionally bears1, 2 or 3 substituents selected from the group consisting of hydroxy,halogeno, cyano, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, phenyl,phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl andbenzoyl, and wherein the phenyl substituent or the phenyl group in aphenyl-containing substituent optionally bears 1 or 2 substituentsselected from the group consisting of halogeno, (1-4C)alkyl and(1-4C)alkoxy;

(o) Q is phenyl which bears a phenyl substituent and optionally bears 1or 2 substituents selected from the group consisting of hydroxy,halogeno, cyano, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy, andwherein the phenyl substituent optionally bears up to 4 substituentsselected from the group consisting of halogeno, trifluoromethyl, cyano,trifluoromethoxy, (1-4C)alkyl and (1-4C)alkoxy;

(p) Q is phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl orphenyl-(2-4C)alkynyl which optionally bears 1, 2 or 3 substituentsselected from the group consisting of halogeno, cyano, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy;

(q) Q is phenyl-(2-4C)alkenyl which optionally bears 1, 2 or 3substituents selected from the group consisting of halogeno, cyano,trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;

(r) Q is phenyl or phenyl-(1-4C)alkyl which bears 1 substituent selectedfrom the group consisting of heteroaryl, heteroaryloxy, heteroarylthio,heteroarylsulphinyl and heteroarylsulphonyl, wherein the heteroarylsubstituent or the heteroaryl group in a heteroaryl-containingsubstituent comprises a 5- or 6-membered monocyclic heteroaryl ringcontaining up to 3 heteroatoms selected from the group consisting ofnitrogen, oxygen and sulphur, and wherein said heteroaryl orheteroaryl-containing substituent optionally bears 1 or 2 substituentsselected from the group consisting of halogeno, (1-4C)alkyl and(1-4C)alkoxy;

(s) Q is phenyl which bears 1 substituent selected from the groupconsisting of heteroaryl, heteroaryloxy, heteroarylthio andheteroarylsulphonyl, wherein the heteroaryl substituent or theheteroaryl group in a heteroaryl-containing substituent is selected fromthe group consisting of thienyl, pyridyl, pyrimidinyl, pyrazolyl,oxazolyl, thiazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl, and whereinsaid heteroaryl or heteroaryl-containing substituent optionally bears 1or 2 substituents selected from the group consisting of halogeno and(1-4C)alkyl;

(t) Q is naphthyl which optionally bears 1 or 2 substituents selectedfrom the group consisting of hydroxy, halogeno, cyano, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy;

(u) Q is a heterocyclic moiety containing up to 2 heteroatoms selectedfrom the group consisting of benzofuranyl, quinolyl, tetrahydroquinolyl,isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl,benzimidazolyl, indazolyl, benzoxazolyl and benzothiazolyl, and Qoptionally bears 1 or 2 substituents selected from the group consistingof halogeno, cyano, trifluromethyl, (1-4C)alkyl and (1-4C)alkoxy;

(v) Q is a heterocyclic moiety containing up to 2 heteroatoms selectedfrom the group consisting of benzofuranyl, quinolyl, tetrahydroquinolyl,isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl,benzimidazolyl, indazolyl, benzoxazolyl, benzothiazolyl, dibenzofuranyland dibenzothienyl, and Q optionally bears 1 or 2 substituents selectedfrom the group consisting of halogeno, cyano, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy;

(w) Q is a heterocyclic moiety containing up to 4 heteroatoms selectedfrom the group consisting of furyl, thienyl, pyridyl, pyrimidinyl,pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,thiadiazolyl and tetrazolyl, and Q optionally bears 1 or 2 substituentsselected from the group consisting of halogeno, cyano, carboxy,carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy,N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl;

(x) Q is a heterocyclic moiety containing up to 2 heteroatoms selectedfrom the group consisting of thienyl, pyridyl, pyrimidinyl, imidazolyl,pyrazolyl, oxazolyl and thiazolyl, and Q optionally bears 1 or 2substituents selected from the group consisting of halogeno,(1-4C)alkyl, (1-4C)alkoxy, phenyl, heteroaryl, phenoxy, phenylthio,phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio,heteroarylsulphinyl, heteroarylsulphonyl, benzyl and benzoyl, whereinthe heteroaryl substituent or the heteroaryl group in aheteroaryl-containing substituent is selected from the group consistingof thienyl, pyridyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, andwherein said phenyl, phenyl-containing, heteroaryl orheteroaryl-containing substituent optionally bears 1 or 2 substituentsselected from the group consisting of halogeno, (1-4C)alkyl and(1-4C)alkoxy; or

(y) Q is a heterocyclic moiety containing up to 2 heteroatoms selectedfrom the group consisting of thienyl, pyridyl, oxazolyl and thiazolyl,and Q bears a substituent selected from the group consisting of phenyl,thienyl, pyridyl, pyrimidinyl, oxazolyl and thiazolyl, which substituentoptionally bears 1 or 2 substituents selected from the group consistingof halogeno, (1-4C)alkyl and (1-4C)alkoxy, and Q optionally bears afurther substituent selected from the group consisting of halogeno and(1-4C)alkyl;

or a pharmaceutically-acceptable salt thereof.

A preferred compound of the invention is an aminoheterocyclic derivativeof the formula I

wherein each of G¹, G² and G³ is CH, or each of G¹ and G² is CH and G³is N, or G¹ is N and each of G² and G³ is CH;

m is 1 or 2 and each R¹ is independently selected from hydrogen, amino,fluoro, chloro, bromo, cyano, methyl, ethyl and methoxy;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -TR.sup.3

in which R² and R³ together form an ethylene group,

L¹ is methylene or ethylene, and T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the ring formed whenR² and R³ are linked optionally bears a substituent selected from thegroup consisting of methyl and ethyl;

A is a direct link to the carbonyl group or A is methylene;

M² is a group of the formula

    (T.sup.2 R.sup.4 ).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 0 or 1, T² is CH or N, T³ is N,

R⁴ is hydrogen, methyl or ethyl, R⁵ is hydrogen, methyl or ethyl, or R⁴and R⁵ together form a methylene, ethylene, trimethylene ormethylenecarbonyl group, or R⁴ is an ethylene group which is linked to amethylene group within L² forming a 5- or 6-membered ring involving R⁴and T², and

L² is methylene, ethylene, trimethylene, methylenecarbonyl or phenylene,

and wherein 1 or 2 methylene groups within L² and the ring formed whenR⁴ and R⁵ are linked optionally bears a substituent selected from thegroup consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl,carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl,pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, methyl, ethyl,carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl,hydroxymethyl, methoxymethyl and benzyl,

and wherein the pyrrolidin-1-ylcarbonyl, piperidinocarbonyl,morpholinocarbonyl, piperazin-1-ylcarbonyl or4-methylpiperazin-1-ylcarbonyl substituent optionally bears a methyl orethyl substituent;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene orcarbonylethylene;

X is thio, sulphinyl, sulphonyl, carbonyl, carbonyloxy or methylene; andQ is phenyl, naphthyl, benzyl, phenethyl, styryl, 2-phenylethynyl,dibenzofuranyl, biphenylyl, pyridylphenyl or pyridylthienyl, and Qoptionally bears 1, 2 or 3 substituents selected from the groupconsisting of hydroxy, amino, fluoro, chloro, bromo, iodo, cyano,trifluoromethyl, nitro, carboxy, carbamoyl, methoxycarbonyl,ethoxycarbonyl, methyl, ethyl, methoxy and ethoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula I

wherein each of G¹,G² and G³ is CH, or each of G¹ and G² is CH and G³ isN, or G¹ is N and each of G² and G³ is CH;

m is 1 or 2 and each R is independently selected from hydrogen, amino,chloro, methyl and ethyl;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is ethylene, and

T¹ is CH or N;

A is a direct link to the carbonyl group or A is methylene;

M² is a group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 0 or 1, T² is N, T³ is N,

R⁴ is hydrogen, R⁵ is hydrogen, or R⁴ and R⁵ together form an ethylenegroup, or R⁴ is an ethylene group which is linked to a methylene groupwithin L² forming a 5- or 6-membered ring involving R⁴ and T², and L² ismethylene, ethylene or phenylene,

and wherein 1 or 2 methylene groups within L² and the ring formed whenR⁴ and R⁵ are linked optionally bears a substituent selected from thegroup consisting of carboxy, methoxycarbonyl, ethoxycarbonyl,pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, methyl, ethyland benzyl,

and wherein the pyrrolidin-1-ylcarbonyl, piperidinocarbonyl,morpholinocarbonyl, piperazin-1-ylcarbonyl or4-methylpiperazin-i-ylcarbonyl substituent optionally bears a methyl orethyl substituent;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene;

X is sulphonyl; and

Q is phenyl, naphthyl, benzyl, phenethyl, styryl, 2-phenylethynyl,dibenzofuranyl, biphenylyl, pyridylphenyl or pyridylthienyl, and Qoptionally bears 1 or 2 substituents selected from the group consistingof fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy and ethoxy; or apharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula Ia wherein each of G¹ and G² is CH;

m is 1 and R is hydrogen;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is methylene or ethylene, and

T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the ring formed whenR² and R³ are linked optionally bears a substituent selected from thegroup consisting of methyl and ethyl;

A is a direct link to the carbonyl group or A is methylene;

M² is a group of the formula

    (T.sup.2 R.sup.4)-L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is CH or N, T³ is N,

R⁴ is hydrogen, methyl or ethyl, R⁵ is hydrogen, methyl or ethyl, or R⁴and R⁵ together form an ethylene group, or R⁴ is an ethylene group whichis linked to a methylene group within L² forming a 5- or 6-membered ringinvolving R⁴ and T², and

L² is methylene, ethylene or trimethylene,

and wherein 1 or 2 methylene groups within L2 and the ring formed whenR⁴ and R⁵ are linked optionally bears a substituent selected from thegroup consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl,N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, methyl, ethyl and benzyl, and wherein thepyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituent optionallybears a methyl or ethyl substituent;

M³ is a direct link to X, or ³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene orcarbonylethylene;

X is sulphonyl; and

Q is phenyl, 2-naphthyl or benzyl which optionally bears 1 or 2substituents selected from the group consisting of fluoro, chloro, bromoand trifluoromethyl;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula I

wherein G is CH or N and each of G¹ and G² is CH;

m is 1 and R¹ is hydrogen;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is methylene or ethylene, and

T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the ring formed when

R² and R³ are linked optionally bears a substituent selected from thegroup consisting of methyl and ethyl;

A is a direct link to the carbonyl group or A is methylene;

M² is a group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is CH or N, T³ is N,

R¹ is hydrogen, methyl or ethyl, R⁵ is hydrogen, methyl or ethyl, or R⁴and R⁵ together form a methylene, ethylene or trimethylene group, or R⁴is an ethylene group which i s linked to a methylene group within L²forming a 5- or 6-membered ring involving R⁴ and T², and

L² is methylene, ethylene or trimethylene

and where 1 or 2 methylene groups within L² and the ring formed when R⁴and R⁵ are linked optionally bears a substituent selected from the groupconsisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl,N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-l-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl, andwherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituentoptionally bears one or two methyl or ethyl substituents;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene orcarbonylethylene;

X is sulphonyl; and

Q is 3- or 4-biphenylyl which optionally bears, in the ring attached toX, 1 or 2 substituents selected from the group consisting of hydroxy,fluoro, chloro, bromo, cyano, trifluoromethyl, methyl, ethyl, methoxyand ethoxy and which optionally bears in the terminal phenyl group up to4 substituents selected from the group consisting of fluoro, chloro,bromo, trifluoromethyl, cyano, trifluoromethoxy, methyl, ethyl, methoxyand ethoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula I wherein G³ is CH or N and each of G¹ and G²is CH;

m is 1 and R¹ is hydrogen;

m¹ is a group of the formula

    NR.sup.2 -L.sup.1 T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is methylene or ethylene, and

T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the ring formed whenR² and R³ are linked optionally bears a substituent selected from thegroup consisting of methyl and ethyl;

A is a direct link to the carbonyl group or A is methylene;

M² is a group of the formula

    (T.sup.2 R.sup.4)-L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is CH or N, T³ is N,

R⁴ is hydrogen, methyl or ethyl, R is hydrogen, methyl or ethyl, or R⁴and R⁵ together form a methylene, ethylene or trimethylene group, or R⁴is an ethylene group which is linked to a methylene group within L²forming a 5- or 6-membered ring involving R⁴ and T², and

L2 is methylene, ethylene or trimethylene,

and wherein 1 or 2 methylene groups within L² and the ring formed whenR⁴ and R⁵ are linked optionally bears a substituent selected from thegroup consisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl,carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl,pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, methyl,ethyl and benzyl, and wherein the pyrrolidin-1-ylcarbonyl orpiperidinocarbonyl substituent optionally bears one or two methyl orethyl substituents;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 (NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene orcarbonylethylene;

X is sulphonyl; and

Q is benzyl, phenethyl, styryl or 2-phenylethynyl which optionally bears1, 2 or 3 substituents selected from the group consisting of fluoro,chloro, bromo, cyano, trifluoromethyl, methyl, ethyl, methoxy andethoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula Ia wherein each of G¹ and G² is CH;

m is 1 and R¹ is hydrogen;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is methylene or ethylene, and

T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the ring formed whenR² and R³ are linked optionally bears a substituent selected from thegroup consisting of methyl and ethyl;

A is a direct link to the carbonyl group or A is methylene;

M² is a group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 T.sup.3 R.sup.5

in which r is 1, T² is CH or N, T³ is N,

R⁴ is hydrogen, methyl or ethyl, R⁵ is hydrogen, methyl or ethyl, or R⁴and R⁵ together form an ethylene group, or R⁴ is an ethylene group whichis linked to a methylene group within L² forming a 5- or 6-membered ringinvolving R⁴ and T², and

L² is methylene, ethylene or trimethylene,

and wherein 1 or 2 methylene groups within L² and the ring formed whenR⁴ and R⁵ are linked optionally bears a substituent selected from thegroup consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl,N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, methyl, ethyl and benzyl, and wherein thepyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituent optionallybears a methyl or ethyl substituent;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6)

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene orcarbonylethylene;

X is sulphonyl; and

Q is 2-thienyl which bears a substituent selected from the groupconsisting of phenyl, thienyl, pyridyl and pyrimidinyl and wherein saidsubstituents optionally bear 1 or 2 substituents selected from the groupconsisting of fluoro, chloro, bromo and methyl;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula I

wherein G³ is CH or N and each of G¹ and G² is CH;

m is 1 and R¹ is hydrogen;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 -R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is methylene or ethylene, and

T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the ring formed whenR² and R³ are linked optionally bears a substituent selected from thegroup consisting of methyl and ethyl;

A is a direct link to the carbonyl group or A is methylene;

M² is a group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is CH or N, T³ is N,

R⁴ is hydrogen, methyl or ethyl, R⁵ is hydrogen, methyl or ethyl, or R⁴and R⁵ together form an ethylene group, or R⁴ is an ethylene group whichis linked to a methylene group within L² forming a 5- or 6-membered ringinvolving R and T , and

L² is methylene, ethylene or trimethylene,

and wherein 1 or 2 methylene groups within L² and the ring formed whenR⁴ and R⁵ are linked optionally bears a substituent selected from thegroup consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl,N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl, andwherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituentoptionally bears a methyl or ethyl substituent;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene orcarbonylethylene;

X is sulphonyl; and

Q is 3- or 4-biphenylyl which optionally bears in the terminal phenylgroup up to 4 substituents selected from the group consisting of fluoro,chloro, bromo, trifluoromethyl, trifluoromethoxy, methyl and methoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula I

wherein G³ is CH or N and each of G¹ and G² is CH;

m is 1 and R¹ is hydrogen;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is methylene or ethylene, and

T¹ is CH or N,

and wherein 1 or 2 methylene groups within L¹ and the ring formed whenR² and R³ are linked option ally bears a substituent selected from thegroup consisting of methyl and ethyl;

A is a direct link to the carbonyl group or A is methylene;

M² is a group of the formula

    (T.sup.2 R.sup.4)-L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is CH or N, T³ is N,

R⁴ is hydrogen, methyl or ethyl, R⁵ is hydrogen, methyl or ethyl, or R⁴and R⁵ together form an ethylene group, or R⁴ is an ethylene group whichis linked to a methylene group within L² forming a 5- or 6-membered ringinvolving R⁴ and T², and

L² is methylene, ethylene or trimethylene,

and wherein 1 or 2 methylene groups within L² and the ring formed whenR⁴ and R⁵ are linked optionally bears a substituent selected from thegroup consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl,N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl, andwherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituentoptionally bears a methyl or ethyl substituent;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene orcarbonylethylene;

X is sulphonyl; and

Q is phenethyl, styryl or 2-phenylethynyl which optionally bears 1, 2 or3 substituents selected from the group consisting of fluoro, chloro,bromo, trifluoromethyl, methyl and methoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula Ia wherein each of G¹ and G² is CH;

m is 1 and R¹ is hydrogen;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is ethylene, and

T¹ is CH or N;

A is a direct link to the carbonyl group;

M² is a group of formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is N and T³ is N,

R⁴ is hydrogen, R⁵ is hydrogen, or R⁴ and R⁵ together form an ethylenegroup, and

L² is ethylene,

and wherein 1 methylene group within L² optionally bears a substituentselected from carboxy, ethoxycarbonyl, N-methylcarbamoyl,piperidinocarbonyl and benzyl;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene;

X is sulphonyl; and

Q is 2-naphthyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula Ia

wherein each of G¹ and G² is CH, G¹ is N and G² is CH, or G¹ is CH andG² is N;

m is I and R¹ is hydrogen;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 -R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is ethylene, and

T¹ is CH or N;

A is a direct link to the carbonyl group;

M² is a group of formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is N and T³ is N,

R⁴ is hydrogen, R⁵ is hydrogen, or R⁴ and R5 together form an ethylenegroup, and

L² is ethylene,

and wherein 1 methylene group within L² optionally bears a substituentselected from carboxy, ethoxycarbonyl, N-methylcarbamoyl,piperidinocarbonyl, methyl and benzyl;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 (NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene;

X is sulphonyl; and

Q is 2-naphthyl which optionally bears I or 2 substituents selected fromthe group consisting of fluoro, chloro, bromo, trifluoromethyl, methyl,methoxy and ethoxy;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula I

wherein each of G ,G and G is CH;

m is 1 and R¹ is hydrogen;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is ethylene, and

T¹ is CH or N;

A is a direct link to the carbonyl group;

M² is a group of formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is N and T³ is N,

R⁴ is hydrogen, R⁵ is hydrogen, or R⁴ and R⁵ together form an ethylenegroup, and

L² is ethylene,

and wherein 1 methylene group within L² optionally bears a substituentselected from carboxy, ethoxycarbonyl, N-methylcarbamoyl,piperidinocarbonyl and benzyl;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene;

X is sulphonyl; and

Q is 4-biphenylyl which bears in the terminal phenyl group 1 or 2substituents selected from fluoro, chloro, bromo, trifluoromethyl andmethyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula I

wherein each of G¹, G² and G³ is CH, G¹ is N and each of G² and G³ isCH, or G³ is N and each of G¹ and G² is CH;

m is 1 and R¹ is hydrogen;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is ethylene, and

T¹ is CH or N;

A is a direct link to the carbonyl group;

M² is a group of formula

    (T.sup.2 R.sup.4 -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T is N and T³ is N,

R⁴ is hydrogen, R⁵ is hydrogen, or R⁴ and R⁵ together form an ethylenegroup, and

L² is ethylene,

and wherein 1 methylene group within L² optionally bears a substituentselected from carboxy, ethoxycarbonyl, N-methylcarbamoyl,piperidinocarbonyl, methyl and benzyl;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene;

X is sulphonyl; and

Q is 4-biphenylyl which bears in the terminal phenyl group 1 or 2substituents selected from fluoro, chloro, bromo, trifluoromethyl andmethyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula I

wherein each of G¹, G² and G³ is CH;

m is 1 and R is hydrogen;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is ethylene, and

T¹ is CH or N;

A is a direct link to the carbonyl group;

M² is a group of formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T is N and T³ is N,

R⁴ is hydrogen, R⁵ is hydrogen, or R⁴ and R⁵ together form an ethylenegroup, and

L² is ethylene,

and wherein 1 methylene group within L² optionally bears a substituentselected from carboxy, ethoxycarbonyl, N-methylcarbamoyl,piperidinocarbonyl and benzyl;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene;

X is sulphonyl; and

Q is styryl which optionally bears 1 or 2 substituents selected from thegroup consisting of fluoro, chloro, bromo, trifluoromethyl and methyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of the formula I

wherein each of G¹, G² and G³ is CH, G¹ is N and each of G² and G³ isCH, or G³ is N and each of G¹ and G² is CH;

m is 1 and R¹ is hydrogen;

M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group,

L¹ is ethylene, and

T¹ is CH or N;

A is a direct link to the carbonyl group;

M² is a group of formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is N and T³ is N,

R⁴ is hydrogen, R⁵ is hydrogen, or R⁴ and R⁵ together form an ethylenegroup, and

L² is ethylene,

and wherein 1 methylene group within L2 optionally bears a substituentselected from carboxy, ethoxycarbonyl, N-methylcarbamoyl,piperidinocarbonyl, methyl and benzyl;

M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6 ).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene;

X is sulphonyl; and

Q is styryl which optionally bears 1 or 2 substituents selected from thegroup consisting of fluoro, chloro, bromo, trifluoromethyl and methyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A specific preferred compound of the invention is the followingaminoheterocyclic derivative of the formula I:

2-(2-naphthalenesulphonamido)-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide,

1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,

2-(2-naphthalenesulphonamido)-N-(1-piperidinocarbonyl-2-{2-[1-(4-pyridyl)piperidin-4-yl]acetamido}ethyl)acetamide,

2-(2-naphthalenesulphonamido)-N-(1-piperidinocarbonyl-2-{2-[4-(4-pyridyl)piperazin-1-yl]acetamido}ethyl)acetamide,ethyl2-(2-naphthalenesulphonamido)-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionate,

1-[1-(2-naphthylsulphonyl)piperidin-4-ylcarbonyl]-4-(4-pyridyl)piperazineor

2-(2-naphthalenesulphonamido)-N-{1-phenyl-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]prop-2-yl}acetamide;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further specific preferred compound of the invention is the followingaminoheterocyclic derivative of the formula I:

4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-1-[(E)-styrylsulphonyl]-piperazine,

1-[(E)-4-chlorostyrylsulphonyl]-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,

1-[(E)-4-methylstyrylsulphonyl]-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,

4-[(E)-4-chlorostyrylsulphonyl]-2-methyl-1-[l-(⁴-pyridyl)piperidin-4-ylcarbonyl]piperazine,

1-(4-biphenylylsulphonyl)-4-[l-(⁴-pyridyl)piperidin-4-ylcarbonyl]-piperazine,

1-(4'-chloro-4-biphenylylsulphonyl)-4-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazineor

1-[(E)-⁴ -chlorostyrylsulphonyl]-4-[l-(⁴-pyrimidinyl)piperidin-4-ylcarbonyl]piperazine;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further specific preferred compound of the invention is the followingaminoheterocyclic derivative of the formula I:

1-(7-chloronaphth-2-ylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,

2-ethoxycarbonyl-4-(2-naphthylsulphonyl)-[1-(⁴-pyridyl)piperidin-4-ylcarbonyl]piperazine or

1-(2-naphthylsulphonyl)-4-[l-(⁴-pyrimidinyl)piperidin-4-ylcarbonyl]-piperazine;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further specific preferred compound of the invention is the followingaminoheterocyclic derivative of the formula I:

1-[(E)-4-fluorostyrylsulphonyl]-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,

1-[(E)-4-bromostyrylsulphonyl]-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-piperazineor

1-(4'-bromo-4-biphenylylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further specific preferred compound of the invention is the followingaminoheterocyclic derivative of the formula I:

1-(⁶ -chloronaphth-2-ylsulphonyl)-4-[1-(⁴-pyridyl)piperidin-4-ylcarbonyl]piperazine,

1-(6-bromonaphth-2-ylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,

1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]piperazine,

4-(2-naphthylsulphonyl)-2-piperidinocarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,

4-(6-chloronaphth-2-ylsulphonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazine,

2-carboxy-4-(6-chloronaphth-2-ylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,

1-(6-chloronaphth-2-ylsulphonyl)-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]piperazine,

4-[1-(2-aminopyrimidin-4-yl)piperidin-4-ylcarbonyl]-1-(6-chloronaphth-2-ylsulphonyl)piperazineor

1-(6-chloronaphth-2-ylsulphonyl)-4-[1-(4-pyridazinyl)piperidin-4-ylcarbonyl]piperazine;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further specific preferred compound of the invention is the followingaminoheterocyclic derivative of the formula I:

4-(6-bromonaphth-2-ylsulphonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazine,

4-(6-bromonaphth-2-ylsulphonyl)-2-carboxy-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,

4-(6-bromonaphth-2-ylsulphonyl)-2-morpholinocarbonyl-1-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazine,

4-(6-chloronaphth-2-ylsulphonyl)-2-methoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazineor

2-carboxy-4-(6-chloronaphth-2-ylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;

or a pharmaceutically-acceptable salt thereof.

An aminoheterocyclic derivative of the formula I or of the formula Ia,or a pharmaceutically-acceptable salt thereof, may be prepared by anyprocess known to be applicable to the preparation ofstructurally-related compounds. Such procedures are provided as afurther feature of the invention and are illustrated by the followingrepresentative processes in which, unless otherwise stated G¹, G², G³,m, R¹, M¹, A, M², M³, X and Q (and any groups defined therein) have anyof the meanings defined hereinbefore, provided that when there is anamino, alkylamino, hydroxy or carboxy group in R¹, M¹, M², M³ or Q thenany such group is protected by a conventional protecting group which maybe removed when so desired by conventional means.

Necessary starting materials may be obtained by standard procedures oforganic chemistry. The preparation of such starting materials isillustrated within the accompanying Examples; alternatively analogousprocedures to those illustrated may be employed by applying no more thanthe ordinary skill of an organic chemist.

(a) For the production of those compounds of the formula I wherein M² isa group of the formula

    (T.sup.2 R.sup.4).sub.4rl -L.sup.2 -T.sup.3 R.sup.5

in which T² is N and r is 1, the reaction, conveniently in the presenceof a suitable base, of an acid of the formula II, or a reactivederivative thereof, with an amine of the formula

    HNR.sup.4 -L.sup.2 -T.sup.3 R.sup.5 -M.sup.3 -X-Q

A suitable reactive derivative of an acid of the formula II is, forexample, an acyl halide, for example an acyl chloride formed by thereaction of the acid and an inorganic acid chloride, for example thionylchloride; a mixed anhydride, for example an anhydride formed by thereaction of the acid and a chloroformate such as isobutyl chloroformate;an active ester, for example an ester formed by the reaction of the acidand a phenol such as pentafluorophenol, an ester such aspentafluorophenyl trifluoroacetate or an alcohol such asN-hydroxybenzotriazole or N-hydroxysuccinimide; an acyl azide, forexample an azide formed by the reaction of the acid and an azide such asdiphenylphosphoryl azide; an acyl cyanide, for example a cyanide formedby the reaction of an acid and a cyanide such as diethylphosphorylcyanide; or the product of the reaction of the acid and a carbodiimidesuch as N,N'-dicyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.

The reaction is conveniently carried out in the presence of a suitablebase such as, for example, an alkali or alkaline earth metal carbonate,alkoxide, hydroxide or hydride, for example sodium carbonate, potassiumcarbonate, sodium ethoxide, potassium butoxide, sodium hydroxide,potassium hydroxide, sodium hydride or potassium hydride, or anorganometallic base such as an alkyl-lithium, for examplen-butyl-lithium, or a dialkylamino-lithium, for example lithiumdi-isopropylamide, or, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine or diazabicyclo-[5.4.0]undec-7-ene. Thereaction is also preferably carried out in a suitable inert solvent ordiluent, for example methylene chloride, chloroform, carbontetrachloride, tetrahydrofuran, 1,2-dimethoxyethane,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one,dimethylsulphoxide or acetone, and at a temperature in the range, forexample, -78° to 150° C., conveniently at or near ambient temperature.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid such ashydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid andan arylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a tert-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

(b) For the production of those compounds of the formula I wherein M² isa group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which T³ is N,

and wherein M³ is a direct link to X, the reaction, conveniently in thepresence of a suitable base as defined hereinbefore, of an amine of theformula III with a compound of the formula Z-X-Q wherein Z is adisplaceable group.

A suitable value for the displaceable group Z is, for example, ahalogeno or sulphonyloxy group, for example a fluoro, chloro, bromo,mesyloxy or 4-tolylsulphonyloxy group.

The reaction is conveniently performed in a suitable inert solvent ordiluent as defined hereinbefore and at a temperature in the range, forexample, 0° C. to 150° C., conveniently at or near ambient temperature.

(c) For the production of those compounds of the formula I wherein M¹ isa group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which T¹ is N,

and wherein A is a direct link to the carbonyl group, the reaction,conveniently in the presence of a suitable base as defined hereinbefore,of an amine of the formula IV with an acid of the formula

    HO.sub.2 C-M.sup.2 -M.sup.3 -X-Q

or a reactive derivative thereof as defined hereinbefore.

The reaction is conveniently performed in a suitable inert solvent ordiluent as defined hereinbefore and at a temperature in the range, forexample, 0° to 150° C., conveniently at or near ambient temperature.

(d) For the production of those compounds of the formula I wherein M² isa group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which T³ is N, and wherein M3 is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which L³ is carbonylmethylene, the reaction, conveniently in thepresence of a suitable base as defined hereinbefore, of an amine of theformula III with an acid of the formula

    HO.sub.2 C-CH.sub.2 -(NR.sup.6).sub.s -X-Q

or a reactive derivative thereof as defined hereinbefore.

The reaction is conveniently performed in a suitable inert solvent ordiluent as defined hereinbefore and at a temperature in the range, forexample, 0° to 150° C., conveniently at or near ambient temperature.

(e) For the production of those compounds of the formula I wherein M² isa group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which T³ is N, and wherein M³ is a direct link to X and X iscarbonylamino, the reaction of an amine of the formula III with anisocyanate of the formula

    OCN-X-Q

The reaction is conveniently performed in a suitable inert solvent ordiluent as defined hereinbefore and at a temperature in the range, forexample, 0° to 60° C., conveniently at or near ambient temperature.

(f) The reaction, conveniently in the presence of a suitable base asdefined hereinbefore, of a compound of the formula V wherein Z is adisplaceable group as defined hereinbefore, with an amine of the formula

    HNR.sup.2 -L.sup.1 -T.sup.1 R.sup.3 -A-CO-M.sup.2 -M.sup.3 -X-Q

The reaction is conveniently performed in a suitable inert solvent ordiluent as defined hereinbefore and at a temperature in the range, forexample, 0° to 150° C., conveniently in the range 15° to 100° C.

(g) For the production of those compounds of the formula I wherein M²,M³ or Q bears a carboxy or carboxy-containing group, the hydrolysis of acompound of the formula I wherein M², M³ or Q bears a(1-4C)alkoxycarbonyl group.

The hydrolysis reaction may conveniently be carried out in aconventional manner using, for example acidic or basic catalysis. Asuitable acid for the acidic hydrolysis of an ester group is, forexample, an inorganic acid such as hydrochloric or sulphuric acid. Asuitable base for the basic hydrolysis of an ester group is, forexample, an alkali or alkaline earth metal hydroxide such as sodiumhydroxide or potassium hydroxide.

The reaction is conveniently performed in a suitable solvent or diluentsuch as an alcohol, for example methanol or ethanol, and at atemperature in the range, for example, 0° to 120° C., conveniently inthe range of 15° to 60° C.

(h) For the production of those compounds of the formula I wherein M²,M³ or Q bears a carbamoyl, N-alkylcarbamoyl or N,N-dialkylcarbamoylgroup, the reaction of a compound of the formula I wherein M², M³ or Qbears a carboxy group, or a reactive derivative thereof as definedhereinbefore, with ammonia or an appropriate alkylamine or dialkylamine.

The reaction is conveniently performed in a suitable inert solvent ordiluent as defined hereinbefore and at a temperature in the range, forexample, 0° to 120° C., conveniently in the range 15° to 60° C.

(i) For the production of those compounds of the formula I wherein Qbears a hydroxy group, the dealkylation of a compound of the formula Iwherein Q bears a (1-4C)alkoxy group.

A suitable dealkylating reagent is, for example, any of the manyreagents known to effect such a transformation. The reaction may becarried out, for example, using an alkali metal (1-4C)alkylsulphide suchas sodium ethanethiolate or, for example, using an alkali metaldiarylphosphide such as lithium diphenylphosphide. Alternatively thereaction may conveniently be carried out using a boron or aluminiumtrihalide such as boron tribromide.

The dealkylation reaction is conveniently performed in a suitable inertsolvent or diluent as defined hereinbefore and at a temperature in therange, for example, -80° to 100° C., conveniently in the range 0° to 50°C.

When a pharmaceutically-acceptable salt of a compound of the formula Iis required, it may be obtained, for example, by reaction of saidcompound with a suitable acid or base using a conventional procedure.

When an optically active form of a compound of the formula I isrequired, it may be obtained, for example, by carrying out one of theaforesaid procedures using an optically active starting material or byresolution of a racemic form of said compound using a conventionalprocedure.

As stated previously, the compounds of the formula I and of the formulaIa are inhibitors of the enzyme Factor Xa. The effects of thisinhibition may be demonstrated using one or more of the standardprocedures set out hereinafter:

a) Measurement of Factor Xa Inhibition

An in vitro assay system was carried out based on the method of Kettneret al., J. Biol. Chem., 1990, 265, 18289-18297, whereby variousconcentrations of a test compound were dissolved in a pH 7.5 buffercontaining 0.5% of polyethylene glycol and incubated at 37° C. withhuman Factor Xa (0.001 Units/ml, 0.3 ml) for 15 minutes. The chromogenicsubstrate S-2765 (KabiVitum AB, 20 μM) was added and the mixture wasincubated at 37° C. for 20 minutes whilst the absorbance at 405 nm wasmeasured. The maximum reaction velocity (Vmax) was determined andcompared with that of a control sample containing no test compound.Inhibitor potency was expressed as an IC₅₀ value.

b) Measurement of Thrombin Inhibition

The procedure of method a) was repeated except that human thrombin(0.005 Units/ml) and the chromogenic substrate S-2238 (KabiVitum AB)were employed.

c) Measurement of Anticoagulant Activity

An in vitro assay whereby human venous blood was collected and addeddirectly to a sodium citrate solution (3.2 g/100 ml, 9 parts blood to 1part citrate solution). Blood plasma was prepared by contrifugation(1000 g, 15 minutes) and stored at 2-4° C. Conventional activatedpartial thromboplastin time (APTT) and prothrombin time (PT) tests werecarried out in the presence of various concentrations of a test compoundand the concentration of test compound required to double the clottingtime, hereinafter referred to as CT2, was determined. In the APTT test,the test compound, blood plasma and APTT reagent were incubated at 37°C. for 3 minutes. Calcium chloride (0.02M) was added and fibrinformation and the time required for a clot to form were determined. Inthe PT test, an analogous procedure was followed except that tissuethromboplastin was used in place of APTT reagent.

d) An ex vivo Assay of Anticoagulant Activity

The test compound was administered intravenously or orally to a group ofAlderley Park Wistar rats. At various times thereafter animals wereanaesthetised, blood was collected and APTT and PT coagulation assaysanalogous to those described hereinbefore were conducted.

e) An in vivo Measurement of Antithrombotic Activity

Thrombus formation was induced using an analogous method to thatdescribed by Vogel et al., Thromb. Research, 1989, 54, 399-410. A groupof Alderley Park Wistar rats was anaesthetised and surgery was performedto expose the vena cava. Two loose sutures were located, 0.7 cm apart,round the inferior vena cava. Test compound was administeredintravenously or orally. At an appropriate time thereafter tissuethromboplastin (1 ml/kg) was administered into the jugular vein and,after 10 seconds, the two sutures were tightened to induce stasis withinthe ligated portion of vena cava. After 10 minutes the ligated tissuewas excised and the thrombus therein was isolated, blotted and weighed.

Although the pharmacological potencies of the compounds of formulae Iand Ia vary with structural changes as expected, in general compounds ofthe formulae I and Ia possess activity at the following concentrationsor doses in at least one of the above tests a) to c):

test a): IC₅₀ (Factor Xa) in the range, for example, 0.001-25 μM;

test b): IC₅₀ (thrombin), for example, greater than 50 μH;

test c): CT2 (PT) in the range, for example, 1-50 μM; CT2 (APTT) in therange, for example, 10-100 μM.

By way of example, the compound of Example 1 as disclosed hereinafterhas an IC₅₀ of 0.3 pH against Factor Xa in test a), an IC₅₀ of greaterthan 100 pH against thrombin in test b) and a CT2 (PT) of 14 μM and CT2(APTT) of 62 μM in test c), and shows an increased clotting timefollowing the intravenous administration of a 10 mg/kg dose in test d)and a reduced thrombus weight following the intravenous administrationof a 5 mg/kg dose in test e).

By way of further example, the compound of Example 39, Compound No. 2,as disclosed hereinafter has an IC of 0.012 μM against Factor Xa in testa), an IC of greater than 100 μM against thrombin in test b), a CT2 (PT)of 1 μM and CT2 (APTT) of 1.8 μM in test c), and shows an increasedclotting time following the intravenous administration of a 5 mg/kg dosein test d) and a reduced thrombus weight following the intravenousadministration of a 5 mg/kg dose in test d).

By way of further example, the compound of Example 41, Compound No. 3,as disclosed hereinafter has an IC₅₀ of 0.01 μM against Factor Xa intest a) and an IC₅₀ of 83 μM against thrombin in test b).

By way of further example, the compound of Example 40, Compound No. 5,as disclosed hereinafter has an IC₅₀ of 0.003 μM against Factor Xa intest a), an IC₅₀ of 34 μM against thrombin in test b), a CT2 (PT) of 0.5μM and CT2 (APTT) of 1.2 μM in test c), and shows an increased clottingtime following the intravenous administration of a 5 mg/kg dose in testd).

By way of further example, the compound of Example 62 as disclosedhereinafter has an IC₅₀ of 0.002 μM against Factor Xa in test a), anIC₅₀ of >10 μM against thrombin in test b), a CT2 (PT) of 0.7 μM in testc), and shows an increased clotting time following the intravenousadministration of a 5 mg/kg dose in test d).

By way of further example, the compound of Example 63 as disclosedhereinafter has an IC₅₀ of 0.008 pH against Factor Xa in test a), anIC50 of >10 μM against thrombin in test b), a CT2 (PT) of 4.6 μM in testc), and shows an increased clotting time following the intravenousadministration of a 5 mg/kg dose in test d) and a reduced thrombusweight following the intravenous administration of a 5 mg/kg dose intest e).

According to a further feature of the invention there is provided apharmaceutical composition which comprises an aminoheterocyclicderivative of the formula I or of the formula Ia, or apharmaceutically-acceptable salt thereof, in association with apharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral use, for example atablet, capsule, aqueous or oily solution, suspension or emulsion; fortopical use, for example a cream, ointment, gel or aqueous or oilysolution or suspension; for nasal use, for example a snuff, nasal sprayor nasal drops; for vaginal or rectal use, for example a suppository;for administration by inhalation, for example as a finely divided powdersuch as a dry powder, a microcrystalline form or a liquid aerosol; forsub-lingual or buccal use, for example a tablet or capsule; or forparenteral use (including intravenous, subcutaneous, intramuscular,intravascular or infusion), for example a sterile aqueous or oilysolution or suspension. In general the above compositions may beprepared in a conventional manner using conventional excipients.

The amount of active ingredient (that is an aminoheterocyclic derivativeof the formulae I or Ia, or a pharmaceutically-acceptable salt thereof)that is combined with one or more excipients to produce a single dosageform will necessarily vary depending upon the host treated and theparticular route of administration. For example, a formulation intendedfor oral administration to humans will generally contain, for example,from 0.5 mg to 2 g of active agent compounded with an appropriate andconvenient amount of excipients which may vary from about 5 to about 98percent by weight of the total composition. Dosage unit forms willgenerally contain about 1 mg to about 500 mg of an active ingredient.

According to a further feature of the invention there is provided anaminoheterocyclic derivative of the formula I or of the formula Ia, or apharmaceutically-acceptable salt thereof, for use in a method oftreatment of the human or animal body by therapy.

The invention also includes the use of such an active ingredient in theproduction of a medicament for use in:

(i) producing a Factor Xa inhibitory effect;

(ii) producing an anticoagulant effect;

(iii) producing an antithrombotic effect;

(iv) treating a Factor Xa mediated disease or medical condition;

(v) treating a thrombosis mediated disease or medical condition;

(vi) treating coagulation disorders; and/or

(vii) treating thrombosis or embolism involving Factor Xa mediatedcoagulation.

The invention also includes a method of producing an effect as definedhereinbefore or treating a disease or disorder as defined hereinbeforewhich comprises administering to a warm-blooded animal requiring suchtreatment an effective amount of an active ingredient as definedhereinbefore.

The size of the dose for therapeutic or prophylactic purposes of acompound of the formulae I or Ia will naturally vary according to thenature and severity of the medical condition, the age and sex of theanimal or patient being treated and the route of administration,according to well known principles of medicine. As mentioned above,compounds of the formulae I or Ia are useful in the treatment orprevention of a variety of medical disorders where anticoagulant therapyis indicated. In using a compound of the formula I for such a purpose,it will generally be administered so that a daily dose in the range, forexample, 0.5 to 500 mg/kg body weight is received, given if required individed doses. In general lower doses will be administered when aparenteral route is employed, for example a dose for intravenousadministration in the range, for example, 0.5 to 50 mg/kg body weightwill generally be used. For preferred and especially preferred compoundsof the invention, in general, lower doses will be employed, for examplea daily dose in the range, for example, 0.5 to 10 mg/kg body weight.

Although the compounds of the formulae I and Ia are primarily of valueas therapeutic or prophylactic agents for use in warm-blooded animalsincluding man, they are also useful whenever it is required to producean anticoagulant effect, for example during the ex-vivo storage of wholeblood or in the development of biological tests for compounds havinganticoagulant properties.

The compounds of the invention may be administered as a sole therapy orthey may be administered in conjunction with other pharmacologicallyactive agents such as a thrombolytic agent, for example tissueplasminogen activator or derivatives thereof or streptokinase. Thecompounds of the invention may also be administered with, for example, aknown platelet aggregation inhibitor (for example aspirin, a thromboxaneantagonist or a thromboxane synthase inhibitor), a known hypolipidaemicagent or a known anti-hypertensive agent.

The invention will now be illustrated in the following Examples inwhich, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(ii) operations were carried out at room temperature, that is in therange 18-25° C. and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Herck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the end-products of the formula I have satisfactory microanalysesand their structures were confirmed by nuclear magnetic resonance (NHR)and mass spectral techniques; unless otherwise stated, CDCl₃ solutionsof the end-products of the formula I were used for the determination ofNMR spectral data, chemical shift values were measured on the deltascale; the following abbreviations have been used: s, singlet; d,doublet; t, triplet; m, multiplet;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, infra-red (IR) or NMR analysis;

(vii) melting points were determined using a Mettler SP62 automaticmelting point apparatus or an oil-bath apparatus; melting points for theend-products of the formula I were generally determined aftercrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture; and

(viii) the following abbreviations have been used:

    ______________________________________                                        DMF      N,N-dimethylformamide;                                                 THF tetrahydrofuran;                                                          DMSO dimethylsulphoxide;                                                      DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.                    ______________________________________                                    

EXAMPLE 1

N-[2-Amino-1-(piperidinocarbonyl)ethyl]-2-(2-naphthalenesulphonamido)acetamidehydrochloride salt (2.6 g) and triethylamine (3.18 ml) were added inturn to a stirred solution of 1-(4-pyridyl)piperidine-4-carbonylchloride (1.54 g) in methylene chloride (20 ml) and the mixture wasstirred at ambient temperature for 16 hours. The mixture was partitionedbetween ethyl acetate and water. The organic phase was washed withwater, dried (HgSO₄) and evaporated. The residue was purified by columnchromatography using a 89:10:1 mixture of ethyl acetate, methanol andammonia as eluent. The material so obtained was triturated under diethylether to give2-(2-naphthalenesulphonamido)-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamideas a foam (1.9 g, 55%);

NMR Spectrum (CD₃ SOCD₃) 1.37-1.76 (m, 1OH), 3.15-3.5 (m, 1OH), 3.6 (s,2H), 4.1-4.2 (d, 2H), 4.9 (t, 1H), 7.1 (d, 2H), 7.6-8.2 (m, 1H), 8.4 (s,1H);

Elemental Analysis Found C, 60.7; H, 6.5; N, 13.2; C₃₁ H₃₈ N₆ O₅ S 0.5H₂O requires C, 60.5; H, 6.3; N, 13.6%.

TheN-[2-amino-1-(piperidinocarbonyl)ethyl]-2-(2-naphthalenesulphonamido)acetamideused as a starting material was obtained as follows:

N-Hydroxybenzotriazole (10.16 g) andN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (14.7 g) were added inturn to a stirred solution of N² -benzyloxycarbonyl-DL-asparagine (20 g)in DHF (200 ml) which had been cooled in an ice-bath. The mixture wasstirred at 0° to 5° C. for 1 hour. Piperidine (7.4 ml) was added and themixture was stirred for 16 hours and allowed to warm to ambienttemperature. The mixture was concentrated by evaporation. Water (500 ml)was added and the precipitate was isolated and dried. There was thusobtained N² -benzyloxycarbonyl-DL-asparagine piperidide (12 g), m.p.159°-162° C.

After repetition of the reaction, the piperidide so obtained (17 g) wasadded to a stirred solution of bis(trifluoroacetoxy)iodobenzene (33 g)in a mixture of DHF (100 ml) and water (100 ml). The mixture was stirredat ambient temperature for 20 minutes. Triethylamine (14.2 ml) was addedand the mixture was stirred for 16 hours. The mixture was acidified bythe addition of 2N aqueous hydrochloric acid and extracted with ethylacetate. The aqueous phase was basified to pH 8 by the addition of 2Naqueous sodium hydroxide solution and extracted with ethyl acetate (3×60ml). The extracts were combined, washed with water, dried (MgSO₄) andevaporated. There was thus obtained1-[3-amino-2-(benzyloxycarbonylamino)propionyl]piperidine as an oil(8.12 g).

Di-tert-butyl dicarbonate (8.75 g) and triethylamine (7.1 ml) were addedin turn to a stirred solution of the piperidine so obtained in methylenechloride (150 ml) and the mixture was stirred at ambient temperature for16 hours. The mixture was partitioned between methylene chloride and 1Naqueous citric acid solution. The organic phase was washed with water,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 1:1 mixture of hexane and ethyl acetate aseluent. There was thus obtained1-[2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionyl]-piperidineas an oil (7.98 g).

A mixture of a portion (4.2 g) of the material so obtained, 10%palladium-on-carbon catalyst (0.3 g) and ethanol (100 ml) was stirredunder an atmosphere of hydrogen for 8 hours. The mixture was filteredand the filtrate was evaporated. The residue was triturated underdiethyl ether to give1-[2-amino-3-(tert-butoxycarbonylamino)-propionyl]piperidine (2.3 g),m.p. 87-90° C.

A solution of N-(2-naphthylsulphonyl)glycine (2.93 g)min DMF (20 ml) wasadded to a stirred mixture of N-hydroxybenzotriazole (1.5 g),N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (2.16 g) and DMF (80 ml)which had been cooled in an ice-bath. The mixture was stirred for 1hour. A solution of1-[2-amino-3-(tert-butoxycarbonylamino)-propionyl]piperidine (2.98 g) inDMF (10 ml) was added and the mixture was allowed to warm to ambienttemperature and stirred for 16 hours. The mixture was partitionedbetween methylene chloride and water. The organic phase was washed withwater, dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using ethyl acetate as eluent. There was thus obtainedN-[2-(tert-butoxycarbonylamino)-1-(piperidinocarbonyl)ethyl]-2-(2-naphthalenesulphonamido)acetamide(3.2 g), m.p. 95-98° C.

A portion (0.5 g) of the material so obtained was suspended in ethylacetate (25 ml) and the mixture was cooled in an ice-bath. Hydrogenchloride gas was led into the reaction mixture for 20 minutes. A clearsolution was formed followed by the deposition of a precipitate. Thesolid was isolated and dried. There was thus obtainedN-[2-amino-1-(piperidinocarbonyl)ethyl]-2-(2-naphthalene-sulphonamido)acetamidehydrochloride salt (0.34 g);

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D) 1.2-1.6 (m, 6H), 2.7-3.1 (m, 2H),3.1-3.25 (t, 2H), 3.3-3.5 (m, 2H), 3.6 (s, 2H), 4.8-5.0 (t, 1H), 6.5-8.1(m, 7H), 8.4 (s, 1H);

Elemental Analysis Found C, 50.9; H, 6.3; N, 11.8; C₂₀ H₂₆ N₄ O₄ S HClH₂ O requires C, 50.7; H, 6.1; N, 11.8%.

The 1-(4-pyridyl)piperidine-4-carbonyl chloride used as a startingmaterial was obtained as follows:

Oxalyl chloride (0.14 ml) and DMF (2 drops) were added in turn to astirred solution of 1-(4-pyridyl)piperidine-4-carboxylic acid[Tetrahedron, 1988, 44, 7095; 0.21 g] in methylene chloride (20 ml). Themixture was stirred at ambient temperature for 4 hours. The mixture wasevaporated and there was thus obtained the required starting materialwhich was used without further purification.

EXAMPLE 2

A solution of 2-naphthylsulphonyl chloride (0.55 g) in methylenechloride (10 ml) was added to a stirred mixture of1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine trihydrochloride salt(0.85 g), triethylamine (3.1 ml) and methylene chloride (80 ml) and theresultant mixture was stirred at ambient temperature for 18 hours. Themixture was partitioned between methylene chloride and water. Theorganic phase was washed with water, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using increasingly polarmixtures of methylene chloride and methanol (100:6 to 100:10) as eluent.There was thus obtained1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazineas a solid (0.727 g);

NHR Spectrum (CD₃ SOCD₃) 1.4-1.65 (m, 4H), 2.75-3.05 (m, 7H), 3.5-3.7(m, 4H), 3.8-3.95 (m, 2H), 6.8 (d, 2H), 7.65-7.8 (m, 3H), 8.05-8.25 (m,5H), 8.45 (d, 1H);

Elemental Analysis Found C, 63.4; H, 6.1; N, 11.5; C₂₅ H₂₈ N₄ O₃ S 0.5H₂O requires C, 63.4; H, 6.1; N, 11.8%.

The 1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine used as a startingmaterial was obtained as follows:

Thionyl chloride (1.6 ml) was added dropwise to a stirred suspension of1-(4-pyridyl)piperidine-4-carboxylic acid (2.17 g) in methylene chloride(30 ml) and the mixture was stirred at ambient temperature for 1 hour.The mixture was evaporated to give 1-(4-pyridyl)piperidine-4-carbonylchloride which was used without further purification.

The material so obtained was suspended in methylene chloride (30 ml) andtriethylamine (7.8 ml) and a solution of 1-tert-butoxycarbonylpiperazine(2.08 g) in methylene chloride (10 ml) were added in turn. The mixturewas stirred at ambient temperature for 4 hours. The mixture waspartitioned between methylene chloride and water. The organic phase waswashed with water, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using increasingly polar mixtures ofmethylene chloride and methanol as eluent (100:5 to 100:13). There wasthus obtained1-(tert-butoxycarbonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-piperazine(2.38 g).

A saturated solution of hydrogen chloride in diethyl ether (25 ml) wasadded to a stirred solution of the 1-tert-butoxycarbonylpiperazine soobtained in methylene chloride (120 ml) and the mixture was stirred atambient temperature for 18 hours. The mixture was evaporated and theresidue was triturated under diethyl ether. There was thus obtained1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine trihydrochloride salt(2.85 g);

NMR Spectrum (CD₃ SOCD₃) 1.5-1.9 (m, 4H), 3.0-3.2 (m, 7H), 3.6-3.85 (m,4H), 4.15-4.3 (m, 2H), 7.2 (d, 2H), 8.2 (d, 2H).

EXAMPLE 3

1,1'-Carbonyldiimidazole (0.089 g) and triethylamine (0.08 ml) wereadded in turn to a solution ofN-[2-amino-1-(piperidinocarbonyl)ethyl]-2-(2-naphthalenesulphonamido)acetamidohydrochloride salt (0.25 g) in DMF (15 ml) which had been cooled in anice-bath. The mixture was stirred for 30 minutes.1-(4-Pyridyl)piperazine (0.089 g) was added and the mixture was stirredat ambient temperature for 16 hours. The mixture was partitioned betweenethyl acetate and water. The organic phase was washed with water, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using ethyl acetate as eluent. There was thus obtained2-(2-naphthalenesulphonamido)-N-{1-piperidinocarbonyl-2-[4-(4-pyridyl)piperazin-1-ylcarbonylamino]-ethyl}acetamideas a foam (0.118 g);

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D) 1.3-1.6 (m, 6H), 3.0-3.1 (m, 1H),3.2-3.6 (m, 15H), 4.8-4.9 (m, 1H), 7.0 (d, 2H), 7.5-7.7 (m, 2H),7.75-7.83 (m, 1H), 7.9-8.1 (m, 3H), 8.1-8.2 (d, 2H), 8.4 (s, 1H);

Elemental Analysis Found C, 58.9; H, 6.4; N, 15.3; C₃₀ H₃₇ N₇ O₅ S 0.25EtAc requires C, 59.1; H, 6.2; N, 15.6%.

EXAMPLE 4

Using an analogous procedure to that described in Example 1 except that2-[1-(4-pyridyl)piperidin-4-yl]acetyl chloride hydrochloride salt wasused in place of 1-(4-pyridyl)piperidine-4-carbonyl chloride and thatthe product was purified by high pressure liquid chromatography using a50:50:0.1 mixture of acetonitrile, water and trifluoroacetic acid aseluent. There was thus obtained2-(2-naphthalenesulphonamido)-N-(1-piperidinocarbonyl-2-{2-[1-(4-pyridyl)piperidin-4-yl]acetamido}ethyl)acetamideas a foam in 18% yield;

NNR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D) 1.0-1.7 (m, 6H), 1.7-2.1 (m, 8H),3.0-3.4 (m, 9H), 3.5-3.6 (s, 2H), 4.1-4.2 (d, 2H), 4.8-4.9 (m, 1H),7.05-7.2 (d, 2H), 7.6-8.2 (m, 8H), 8.4-8.5 (s, 1H);

Elemental Analysis Found C, 52.8; H, 5.4; N, 11.4; C₃₂ H₄₀ N₆ O₅ S CF₃CO₂ H H₂ O requires C, 53.0; H, 5.8; N, 10.9%.

The 2-[1-(4-pyridyl)piperidin-4-yl]acetyl chloride hydrochloride saltused as a starting material was obtained as follows:

Triethyl phosphonoacetate (19.8 ml) was added dropwise to a stirredsuspension of sodium hydride (50% dispersion in mineral oil, 4.8 g) indimethoxyethane (300 ml) which had been cooled in an ice-bath and themixture was stirred at 0° to 5° C. for 1 hour. 1-Benzyl-4-piperidone(17.85 ml) was added dropwise and the mixture was stirred at ambienttemperature for 16 hours. The mixture was partitioned between diethylether and water. The organic phase was washed with water and with brine,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 3:2 mixture of hexane and ethyl acetate. Therewas thus obtained 1-benzyl-4-(ethoxycarbonylmethylene)piperidine (5.52g).

A mixture of the material so obtained, 10% palladium-on-carbon catalyst(1 g) and ethanol (250 ml) was stirred under an atmosphere of hydrogenfor 6 hours. The mixture was filtered to give ethyl2-(piperidin-4-yl)acetate as an oil (3.31 g) which was used withoutfurther purification;

NMR Spectrum (CDCl₃) 1.0-1.2 (m, 2H), 1.25 (t, 3H), 1.7 (s, 2H), 1.9 (m,1H), 2.2 (d, 2H), 2.6 (m, 2H), 3.05 (m, 2H), 4.0 (m, 2H).

A mixture of a portion (3.25 g) of the material so obtained,4-chloropyridine hydrochloride (2.85 g), triethylamine (5.28 ml) andxylene (100 ml) was stirred and heated to reflux for 16 hours. Themixture was cooled to ambient temperature and filtered. The filtrate wasevaporated and the residue was partitioned between methylene chlorideand water. The organic phase was washed with water, dried (MgSO₄) andevaporated. The residue was purified by column chromatography using a10:1 mixture of methylene chloride and methanol as eluent. There wasthus obtained ethyl 2-[1-(4-pyridyl)piperidin-4-yl]acetate as an oil(2.15 g).

A mixture of the material so obtained, 1N aqueous hydrochloric acid(35.5 ml) and dioxan (100 ml) was stirred and heated to 95° C. for 3hours. The mixture was evaporated and the residue was freeze-dried togive 2-[1-(4-pyridyl)piperidin-4-yl]acetic acid hydrochloride salt (2.3g), m.p. 105°-108° C.

Using an analogous procedure to that described in the portion of Example1 which is concerned with the preparation of starting materials, theacetic acid was reacted with oxalyl chloride to give2-[1-(4-pyridyl)piperidin-4-yl]acetyl chloride hydrochloride salt inquantitative yield.

EXAMPLE 5

Using an analogous procedure to that described in Example 1 except that2-[4-(4-pyridyl)piperazin-1-yl]acetyl chloride was used in place of1-(4-pyridyl)piperidine-4-carbonyl chloride. There was thus obtained2-(2-naphthalenesulphonamido)-N-(1-piperidinocarbonyl-2-{2-[4-(4-pyridyl)piperazin-1-yl]acetamido}ethyl)acetamideas a foam in 6% yield;

NMR Spectrum (CD₃ SOCD₃) 1.3-1.6 (m, 6H), 2.9-3.05 (s, 2H), 3.1-3.7 (m,14H), 4.8-5.0 (t, 1H), 7.0-7.2 (d, 2H), 7.6-8.2 (m, 9H), 8.4 (s, 1H);

Elemental Analysis Found C, 57.4; H, 6.2; N, 14.5; C₃₁ H₃₉ N₇ O₅ S 1.5H₂O requires C, 57.4; H, 6.5; N, 15.1%.

The 2-[4-(4-pyridyl)piperazin-1-yl]acetyl chloride used as a startingmaterial was obtained as follows:

Sodium hydride (50% dispersion in mineral oil, 1.9 g) was addedportionwise to a stirred mixture of 1-(4-pyridyl)piperazine (3 g) andDMF (20 ml) and the mixture was stirred at ambient temperature for 1hour. Tert-butyl bromoacetate (6.5 ml) was added dropwise and themixture was stirred for 18 hours. The mixture was partitioned betweenethyl acetate and water. The organic phase was washed with water, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using a 17:3 mixture of methylene chloride and methanolas eluent. There was thus obtained tert-butyl2-[4-(4-pyridyl)piperazin-1-yl]acetate as a solid (2.85 g).

A mixture of the material so obtained and trifluoroacetic acid (7 ml)was stirred at ambient temperature for 18 hours. The mixture wasevaporated to give 2-[4-(4-pyridyl)piperazin-1-yl]acetic acid inquantitative yield;

NMR Spectrum (CD₃ SOCD₃) 3.35-3.5 (m, 4H), 3.9-4.05 (m, 4H), 4.1 (s,2H), 7.25 (d, 2H), 8.35 (d, 2H).

A mixture of the material so obtained (2.27 g), oxalyl chloride (1.5ml), DMF (3 drops) and methylene chloride (20 ml) was stirred at ambienttemperature for 4 hours. The mixture was evaporated to give2-[4-(4-pyridyl)piperazin-1-yl]acetyl chloride which was used withoutfurther purification.

EXAMPLE 6

Triethylamine (0.77 ml) was added to a stirred mixture of ethyl2-amino-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionatedihydrochloride salt (1 g), succinimido2-(2-naphthalenesulphonamido)acetate (0.92 g) and methylene chloride (50ml) which had been cooled in an ice-bath. The mixture was allowed towarm to ambient temperature and was stirred for 4 hours. The mixture waspartitioned between methylene chloride and water. The organic phase waswashed with water, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using a 4:1 mixture of ethyl acetateand methanol as eluent. There was thus obtainedN-{1-ethoxycarbonyl-2-[1-(4-pyridyl)-piperidin-4-ylcarbonylaminoethyl}-2-(2-naphthalenesulphonamido)-acetamide as a foam (0.203 g);

NMR Spectrum (CD₃ SOCD₃) 1.1-1.2 (t, 3H), 1.4-1.8 (m, 4H), 2.2-2.4 (m,1H), 2.7-3.0 (t, 2H), 3.5 (s, 2H), 3.8-4.1 (m, 4H), 4.2-4.4 (t, 1H),6.7-6.8 (d, 2H), 7.6-8.3 (m, 1H), 8.4 (s, 1H);

Elemental Analysis Found C, 55.7; H, 6.0; N, 11.1; C₂₈ H₃₃ N₅ O₆ S 2H₂ Orequires C, 55.5; H, 6.1; N, 11.6%.

The ethyl 2-amino-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionatedihydrochloride salt used as a starting material was obtained asfollows:

N² -Benzyloxycarbonyl-DL-asparagine (25 g) was added to a stirredsolution of bis(trifluroacetoxy)iodobenzene (60.6 g) in a mixture of DMF(350 ml) and water (350 ml). The mixture was stirred at ambienttemperature for 15 minutes. Pyridine (15 ml) was added and the mixturewas stirred for 16 hours. The mixture was evaporated and the residue waspartitioned between water and diethyl ether. The aqueous layer wasevaporated to give an oil mixed with a solid. The solid was isolated,washed with diethyl ether and dried. There was thus obtained3-amino-2-(benzyloxycarbonylamino)propionic acid (6.3 g).

A portion (3 g) of the material so obtained was added to a stirredmixture of thionyl chloride (1.01 ml) and ethanol (100 ml) which hadbeen cooled to -10° C. The mixture was allowed to warm to ambienttemperature and was stirred for 16 hours. The mixture was evaporated andthe residue was triturated under diethyl ether. There was thus obtainedethyl 3-amino-2-(benzyloxycarbonylamino)propionate hydrochloride salt(3.45 g);

NMR Spectrum (CD₃ SOCD₃) 1.1-1.25 (t, 3H), 3.0-3.2 (m, 2H), 4.05-4.2 (q,2H), 4.3-4.5 (m, 1H), 5.1 (s, 2H), 7.3 (m, 5H), 7.8-7.9 (d, 1H), 8.3 (s,2H).

Triethylamine (0.7 ml) was added to a stirred mixture of ethyl3-amino-2-(benzyloxycarbonylamino)propionate hydrochloride salt (0.5 g),1-(4-pyridyl)piperidine-4-carbonyl chloride (0.45 g) and methylenechloride (20 ml) and the resultant mixture was stirred at ambienttemperature for 16 hours. The mixture was partitioned between methylenechloride and water. The organic phase was washed with brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using increasingly polar mixtures of ethyl acetate andmethanol as eluent. There was thus obtained ethyl2-(benzyloxycarbonylamino)-3-[1-(4-pyridyl)piperidin-4-ylcarbonyl-amino]propionate(0.5 g).

After repetition of the previous step, a mixture of the material soobtained (2 g), 10% palladium-on-carbon catalyst (0.2 g), 1N aqueoushydrochloric acid (8.8 ml) and ethanol (50 ml) was stirred under anatmosphere of hydrogen for 6 hours. The mixture was filtered and thefiltrate was evaporated. There was thus obtained ethyl2-amino-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionatedihydrochloride salt (2.48 g);

NMR Spectrum (CD₃ SOCD₃) 1.2-1.3 (t, 3H), 1.5-1.7 (m, 2H), 1.8-2.0 (m,2H), 2.6-2.7 (m, 1H), 3.2-3.4 (t, 2H), 4.0-4.3 (m, 6H), 7.15-7.82 (d,2H), 8.1-8.2 (d, 2H), 8.5-8.65 (t, 1H).

The succinimido 2-(2-naphthalenesulphonamido)acetate used as a startingmaterial was obtained as follows:

A solution of N,N'-dicyclohexylcarbodiimide (4.12 g) in ethyl acetate(50 ml) was cooled to 0° C. and added to a stirred mixture ofN-(2-naphthylsulphonyl)glycine (5.3 g), N-hydroxysuccinimide (2.3 g) andethyl acetate which had been cooled to 0° C. The mixture was stirred at0° C. for 1 hour, allowed to warm to ambient temperature and stirred for16 hours. The mixture was recooled to 0° C. for 1 hour and filtered. Thefiltrate was evaporated and the residue was recrystallised from amixture of hexane and ethyl acetate. There was thus obtained therequired starting material (6.2 g);

NMR Spectrum (CD₃ SOCD₃) 2.8 (m, 4H), 4.25 (d, 2H), 7.6-7.75 (m, 2H),7.8-7.9 (m, 1H), 8.0-8.2 (m, 3H), 8.45 (s, 1H), 8.6 (t, 1H).

EXAMPLE 7

Using an analogous procedure to that described in Example 2,2-naphthylsulphonyl chloride was reacted with ethyl2-amino-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionatedihydrochloride salt to give ethyl 2-(2-naphthalenesulphonamido)-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionate as a foam in 37%yield;

NMR Spectrum (CD₃ SOCD₃) 1.1-1.2 (t, 3H), 1.3-1.7 (m, 4H), 2.1-2.3 (m,1H), 2.7-2.9 (m, 2H), 3.1-3.9 (m, 6H), 3.9-4.1 (t, 1H), 6.7-6.8 (d, 2H),7.6-8.2 (m, 11H), 8.35 (s, 1H);

Elemental Analysis Found C, 59.8; H, 6.4; N, 10.3; C₂₆ H₃ N₄ O₅ S 0.75H₂O requires C, 59.6; H, 6.0; N, 10.7%.

EXAMPLE 8

A mixture ofN-{1-ethoxycarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}-2-(2-naphthalenesulphonamido)acetamide(0.1 g), methylamine (33% solution in ethanol, 0.2 ml) and ethanol (5ml) was stirred at ambient temperature for 2 hours. The precipitate wasisolated and purified by column chromatography using increasingly polarmixtures of ethyl acetate and methanol as eluent. There was thusobtained N-methyl-2- [2-(2-naphthalenesulphonamido)acetamido]-3-[-(4-pyridyl)piperidin-4-ylcarbonylamino]propionamide(0.01 g);

Elemental Analysis Found C, 57.6; H, 6.1; N, 13.9; C₂₇ H₃₂ N₆ O₅ 0.5 H₂O 0.5EtOH requires C, 57.5; H, 6.1; N, 14.3%.

EXAMPLE 9

A mixture ofN-{1-ethoxycarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino}ethyl)-2-(2-naphthalenesulphonamido)acetamide(0.15 g), 0.1N aqueous sodium hydroxide solution (5.3 ml) and methanol(3 ml) was stirred at ambient temperature for 2 hours. The basicsolution was neutralised by the addition of 0.1N aqueous hydrochloricacid (5.3 ml) and evaporated. The residue was triturated under diethylether. There was thus obtained2-[2-(2-naphthalenesulphonamido)acetamido]-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionicacid (0.123 g);

NMR Spectrum (CD₃ SOCD₃) 1.4-1.65 (m, 2H), 1.6-1.75 (m, 2H), 2.3-2.5 (m,1H), 2.8-3.0 (t, 2H), 3.25-3.4 (m, 2H), 3.85-3.95 (d; 2H), 4.0-4.15 (m,1H), 6.7-6.9 (S, 2H), 7.6-8.4 (m, 10H), 8.4 (s, 1H);

Elemental Analysis Found C, 46.7; H, 4.5; N, 10.3; C₂₆ H₂₉ N₅ O₆ S 2NaClH₂ O requires C, 46.3; H, 4.6; N, 10.4%.

EXAMPLE 10

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with1-[3-amino-2-(2-naphthalenesulphonamido)propionyl]piperidinehydrochloride salt to giveN-[2-(2-naphthalenesulphonamido)-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)-piperidine-4-carboxamidein 17% yield;

Elemental Analysis Found C, 61.4; H, 6.8; N, 12.1; C₂₉ H₃₅ N₅ O₄ S H₂ Orequires C, 61.3; H, 6.5; N, 12.3%.

The 1-[3-amino-2-(2-naphthalenesulphonamido)propionyl]piperidinehydrochloride salt used as a starting material was obtained as follows:

Triethylamine (3.1 ml) was added to a stirred mixture of2-naphthylsulphonyl chloride (1.67 g),1-[2-amino-3-(tert-butoxycarbonylamino)propionyl]piperidine (2 g) andDMF (25 ml) and the mixture was stirred at ambient temperature for 16hours. The mixture was partitioned between ethyl acetate and water. Theorganic phase was washed with brine, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using increasingly polarmixtures of hexane and ethyl acetate as eluent. There was thus obtained1-[3-(tert-butoxycarbonylamino)-2-(2-naphthalenesulphonamido)-propionyl]piperidineas a solid (2.6 g).

The compound so obtained was suspended in ethyl acetate and the mixturewas cooled in an ice-bath. Hydrogen chloride gas was led into themixture for 1 hour. A clear solution was formed followed by thedeposition of a precipitate which was isolated. There was thus obtained1-[3-amino-2- (2-naphthalenesulphonamido)propionyl]piperidinehydrochloride salt as a foam (2 g) which was used without furtherpurification.

EXAMPLE 11

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted withN-[2-amino-2-(piperidinocarbonyl)ethyl]-2-(2-naphthalenesulphonamido)-acetamideto give2-(2-naphthalenesulphonamido)-N-{2-piperidino-carbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamidein 41% yield, m.p. 200°-202° C.;

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D) 1.1-1.8 (m, 9H), 3.0-3.6 (m, 12H),4.0-4.2 (m, 2H), 4.8-5.0 (t, 1H), 7.0-7.2 (s, 2H), 7.6-7.8 (m, 2H),7.8-7.9 (m, 1H), 8.0-8.3 (m 5H), 8.4-8.5 (s, 1H);

Elemental Analysis Found C, 61.1; H, 6.4; N, 13.7; C₃₁ H₃₈ N₆ O₅ Srequires C, 61.4; H, 6.3; N, 13.9%.

TheN-[2-amino-2-(piperidinocarbonyl)ethyl]-2-(2-naphthalene-sulphonamido)acetamideused as a starting material was obtained as follows:

A mixture of 1-[3-amino-2-(benzyloxycarbonylamino)propionyl]-piperidine(2 g), succinimido 2-(2-naphthalenesulphonamido)acetate (2.4 g) andethyl acetate (25 ml) was stirred at ambient temperature for 12 hours.The mixture was partitioned between ethyl acetate and water. The organicphase was washed with water, dried (MgSO₄) and evaporated. The residuewas purified by column chromatography using ethyl acetate as eluent.There was thus obtainedN-[2-(benzyloxy-carbonylamino)-2-(piperidinocarbonyl)ethyl]-2-(2-naphthalene-sulphonamido)acetamideas a foam (1.83 g).

A mixture of the material so obtained, 10% palladium-on-carbon catalyst(0.3 g) and ethanol (40 ml) was stirred under an atmosphere of hydrogenfor 8 hours. The mixture was filtered and the filtrate was evaporated.The residue was purified by column chromatography using a 1:1 mixture ofhexane and ethyl acetate as eluent. There was thus obtainedN-[2-amino-2-(piperidinocarbonyl)-ethyl]-2-(2-naphthalenesulphonamido)acetamide(0.52 g) which was used without further purification.

EXAMPLE 12

The procedure described in Example 2 was repeated except that1-naphthylsulphonyl chloride was used in place of 2-naphthylsulphonylchloride. There was thus obtained1-(1-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 52% yield;

NMR Spectrum (CD₃ SOCD₃) 1.4-1.7 (m, 4H), 2.75-2.95 (m, 3H), 3.0-3.2 (m,4H), 3.45-3.65 (m, 4H), 3.8-3.95 (m, 2H), 6.75 (d, 2H), 7.6-7.8 (m, 3H),8.0-8.2 (m, 4H), 8.35 (d, 1H), 8.7 (d, 1H);

Elemental Analysis Found C, 62.2; H, 6.1; N, 11.3; C₂₅ H₂₈ N₄ O₃ S H₂ Orequires 62.2; H, 6.2; N, 11.6%.

EXAMPLE 13

N-Methylmorpholine (0.095 g) and isobutyl chloroformate (0.13 g) wereadded in turn to a stirred suspension of1-(2-naphthylsulphonyl)piperidine-4-carboxylic acid (0.3 g) in THF (6ml) which had been cooled to -10° C. The mixture was stirred at -10° C.for 30 minutes. A solution of 1-(4-pyridyl)piperazine (0.155 g) in DMF(3 ml) was added and the mixture was stirred at ambient temperature for18 hours. The mixture was evaporated and the residue was purified bycolumn chromatography using a 22:3 mixture of methylene chloride andmethanol as eluent. There was thus obtained1-1-(2-naphthylsulphonyl)piperidin-4-ylcarbonyl]-4-(4-pyridyl)piperazineas a solid (0.07 g);

NMR Spectrum (CD₃ SOCD₃) 1.5-1.75 (m, 4H), 2.3-2.45 (m, 2H), 2.5-2.65(m, 1H), 3.5-3.75 (m, 1OH), 7.05 (d, 2H), 7.6-7.75 (m, 3H), 8.0-8.2 (m,5H), 8.35 (d, 1H).

The 1-(2-naphthylsulphonyl)piperidine-4-carboxylic acid used as astarting material was obtained as follows:

A solution of ethyl piperidine-4-carboxylate (1.02 ml) in methylenechloride (5 ml) was added to a stirred mixture of 2-naphthylsulphonylchloride (1.5 g), triethylamine (4 ml) and methylene chloride (10 ml)which had been cooled to 5° C. The mixture was stirred at ambienttemperature for 18 hours. The mixture was evaporated and the residue waspartitioned between ethyl acetate and water. The organic phase waswashed with 2N aqueous hydrochloric acid and water, dried (MgSO₄) andevaporated. There was thus obtained ethyl1-(2-naphthylsulphonyl)piperidine-4-carboxylate (1.95 g).

A mixture of the material so obtained, potassium hydroxide (0.62 g) andethanol (18 ml) was stirred and heated to reflux for 4 hours. Themixture was evaporated and the residue was partitioned between methylenechloride and water. The organic phase was dried (MgSO₄) and evaporated.There was thus obtained 1-(2-naphthylsulphonyl)piperidine-4-carboxylicacid (1.35 g);

NMR Spectrum (CD₃ SOCD₃) 1.5-1.7 (m, 2H), 1.8-1.95 (m, 2H), 2.2-2.3 (m,1H), 2.45-2.55 (m, 2H), 3.5-3.6 (m, 2H), 7.65-7.8 (m, 3H), 8.05-8.25 (m,3H), 8.45 (d, 1H).

EXAMPLE 14

N,N'-Dicyclohexylcarbodiimide (0.5 g) was added to a stirred mixture ofN-(2-amino-3-phenylpropyl)-1-(4-pyridyl piperidine-4-carboxamide (1.08g), N-(2-naphthylsulphonyl)glycine (0.85 g) N-hydroxybenzotriazole (0.34g), N-methylmorpholine (0.71 ml) and DMF (20 ml) which had been cooledto 5° C. The mixture was stirred at ambient temperature for 18 hours.The mixture was evaporated and the residue was purified by columnchromatography using increasingly polar mixtures of methylene chlorideand methanol (20:1 to 20:3) as eluent. There was thus obtained2-(2-naphthalenesulphonamido)-N-{1-phenyl-3-[1-(4-pyridyl)piperidin-4-ylcarbonylaminolprop-2-yl}acetamideas a solid (0.52 g);

NMR Spectrum (CD₃ SOCD₃) 1.5-1.7 (m, 2H), 1.75-1.9 (m, 2H), 2.4-2.65 (m,4H), 2.9-3.4 (m, 6H), 3.85-4.0 (m, 1H), 4.0-4.15 (m, 2H), 7.0-7.2 (m,6H), 7.55-7.65 (m, 3H), 7.75 (m, 1H), 7.9-8.1 (m, 5H), 8.35 (d, 1H).

The N-(2-amino-3-phenylpropyl)-1-(4-pyridyl)piperidine-4-carboxamideused as a starting material was obtained as follows:

Using an analogous procedure to that described in J. Chem. Res. (S),1992, 391, N² tert-butoxycarbonyl-DL-phenylalanine was converted in foursteps into 1-amino-2-(tert-butoxycarbonylamino)-3-phenylpropane.

Using an analogous procedure to that described in the second paragraphof the portion of Example 2 which is concerned with the preparation ofstarting materials, 1-(4-pyridyl)piperidine-4-carbonyl chloride wasreacted with 1-amino-2-(tert-butoxycarbonylamino)-3-phenylpropane togiveN-[2-(tert-butoxycarbonylamino)-3-phenylpropyl]-1-(4-pyridyl)piperidine-4-carboxamidein 39% yield.

A mixture of the material so obtained (0.95 g) and trifluoroacetic acid(2 ml) was stirred at ambient temperature for 18 hours. The mixture wasevaporated and the residue was triturated under diethyl ether. There wasthus obtainedN-(2-amino-3-phenylpropyl)-1-(4-pyridyl)piperidine-4-carboxamide (0.9 g)which was used without further purification;

NMR Spectrum (CD₃ SOCD₃) 1.5-1.7 (m, 2H), 1.85-2.0 (m, 2H), 2.75-3.0 (m,2H), 3.1-3.5 (m, 6H), 4.15-4.3 (m, 2H), 7.15-7.4 (m, 7H), 8.2-8.3 (m,2H).

EXAMPLE 15

Using an analogous procedure to that described in Example 2 except thatDMF was used in place of methylene chloride as the reaction solvent,1-{2-[4-(4-pyridyl)piperazin-1-yl]acetyl}piperazine was reacted with2-naphthylsulphonyl chloride to give1-(2-naphthylsulphonyl)-4-{2-[4-(4-pyridyl)piperazin-1-yl]acetyl)}piperazinein 22% yield;

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D) 2.4-2.5 (m, 4H), 2.9-3.05 (m, 4H),3.15 (s, 2H), 3.3-3.45 (m, 4H), 3.45-3.65 (m, 4H), 6.95 (d, 2H),7.5-7.75 (m, 3H), 7.95-8.2 (m, 5H), 8.4 (s, 1H);

Elemental Analysis Found C, 62.1; H, 6.1; N, 14.4; C₂₅ H₂₉ N₅ O₃ Srequires C, 62.6; H, 6.1; N, 14.6%.

The 1-{2-[4-(4-pyridyl)piperazin-1-yl]acetyl}piperazine used as astarting material was obtained as follows:

N,N'-Dicyclohexylcarbodiimide (0.84 g) was added to a stirred mixture of2-[4-(4-pyridyl)piperazin-1-yl]acetic acid (1 g),1-(tert-butoxycarbonyl)piperazine (0.67 g), N-hydroxybenzotriazole(0.382 g), N-methylmorpholine (0.79 ml) and DMF (30 ml) which had beencooled to 5° C. The mixture was stirred at ambient temperature for 18hours. The mixture was evaporated and the residue was purified by columnchromatography using a 17:3 mixture of methylene chloride and methanolas eluent. There was thus obtained 1-(tert-butoxycarbonyl)-4-{2-[⁴-(4-pyridyl)piperazin-1-yl]acetyl}piperazine as a foam (0.87 g).

A mixture of a portion (0.75 g) of the material so obtained,trifluoroacetic acid (2 ml) and methylene chloride (5 ml) was stirred atambient temperature for 4 hours. The mixture was evaporated to give1-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]piperazine in quantitativeyield;

NMR Spectrum (CD₃ SOCD₃) 3.05-3.25 (m, 4H), 3.55-3.7 (m, 2H), 3.7-3.8(m, 2H), 3.9-ethyl]-2-(2-naphthalenesulphonamido)acetamide]-4.1 (m, 4H),4.3 (s, 2H), 7.3 (d, 2H), 8.4 (d, 2H), 9.35 (s, 2H).

EXAMPLE 16

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted withN-[3-amino-1-(piperidinocarbonyl)propyl]-2-(2-naphthalenesulphonamido)acetamidehydrochloride salt to give2-(2-naphthalenesulphonamido)-N-{1-piperidinocarbonyl-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-propyl}acetamidein 17% yield;

NMR Spectrum (CD₃ SOCD₃) 1.3-1.8 (m, 12H), 2.3-2.5 (m, 1H), 2.7-3.1 (m,4H), 3.2-3.45 (m, 4H), 3.5-3.6 (m, 2H), 3.8-4.0 (m, 2H), 4.6-4.7 (m,1H), 6.7-6.85 (m, 2H), 7.6-7.8 (m, 3H), 7.8-7.9 (m, 1H), 8.0-8.35 (m,7H), 8.4 (s, 1H);

Elemental Analysis Found C, 59.6; H, 6.6; N, 13.0; C₃₂ H₄₀ N₆ O₅ S1.25H₂ O requires C, 59.8; H, 6.6; N, 13.1%.

TheN-[3-amino-1-(piperidinocarbonyl)propyl]-2-(2-naphthalenesulphonamido)acetamidehydrochloride salt used as a starting material was obtained as follows:

1,1'-Carbonyldiimidazole (3.95 g) was added to a stirred solution of N²-benzyloxycarbonyl-DL-glutamine (8.47 g) in DHF (60 ml) and the mixturewas stirred at ambient temperature for 15 minutes. The mixture wascooled to 5° C. and piperidine (4.82 ml) was added dropwise. The mixturewas allowed to warm to ambient temperature over 1 hour. The mixture waspartitioned between ethyl acetate and 2N aqueous hydrochloric acid. Theorganic phase was washed with water and with brine, dried (MgSO₄) andevaporated. The residue was purified by column chromatography using a9:1 mixture of ethyl acetate and methanol as eluent. There was thusobtained N-benzyloxycarbonyl-DL-glutamine piperidide (4.78 g), m.p.136-138° C.

Using analogous procedures to those described in the second, third andfourth paragraphs of the portion of Example 1 which is concerned withthe preparation of starting materials, the DL-glutamine piperidide wasconverted into 1-[2-amino-4-(tert-butoxycarbonylamino)butyryl]piperidinein 14% yield. 1,1'-Carbonyldiimidazole (0.31 g) was added to a stirredsolution of N-(2-naphthylsulphonyl)glycine (0.446 g) in DMF (5 ml) andthe mixture was stirred at ambient temperature for 30 minutes. Themixture was cooled to 5° C. and1-[2-amino-4-(tert-butoxycarbonylamino)butyryl]piperidine (0.546 g) wasadded. The mixture was stirred at ambient temperature for 6 hours. Themixture was partitioned between ethyl acetate and 1M aqueous citric acidsolution. The organic phase was washed with water and with brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using a 1:1 mixture of methylene chloride and ethylacetate as eluent. There was thus obtainedN-[3-(tert-butoxycarbonylamino)-1-(piperidinocarbonyl)propyl]-2-(2-naphthalenesulphonamido)acetamideas a solid (0.607 g).

The material so obtained was suspended in ethyl acetate (50 ml) and themixture was cooled in an ice-bath. Hydrogen chloride gas was led intothe mixture for 5 minutes. A clear solution was obtained followed by thedeposition of a precipitate. The mixture was evaporated to giveN-[3-amino-1-(piperidinocarbonyl)propyl]-2-(2-naphthalenesulphonamido)acetamidehydrochloride salt (0.528 g) which was used without furtherpurification.

EXAMPLE 17

N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride salt (0.575g) was added to a stirred mixture of(3S)-3-(2-naphthalenesulphonamido)-3-(piperidinocarbonyl)propionic acid(1.17 g), N-hydroxybenzotriazole (0.405 g), triethylamine (0.417 ml) andDMF (10 ml) and the mixture was stirred at ambient temperature for 30minutes. 1-(4-Pyridyl)piperazine (0.489 g) was added and the mixture wasstirred at ambient temperature for 16 hours. The mixture was partitionedbetween ethyl acetate and water. The organic phase was washed with waterand with brine, dried (MgSO₄) and evaporated. The residue was purifiedby column chromatography using increasingly polar mixtures of methylenechloride and methanol as eluent. There was thus obtained1-[(3S)-3-(2-naphthalenesulphonamido)-3-(piperidinocarbonyl)propionyl]-4-(4-pyridyl)piperazineas a solid (0.407 g);

NMR Spectrum (CDCl₃) 0.8-1.1 (m, 2H), 1.2-1.5 (m, 4H), 2.5-2.8 (m, 2H),3.0-3.2 (m, 1H), 3.2-3.45 (m, 7H), 3.5-3.7 (m, 3H), 3.75-3.9 (m, 1H),4.6-4.7 (m, 1H), 6.2-6.4 (m, 1H), 6.6-6.65 (m, 2H), 7.5-8.0 (m, 6H),8.3-8.4 (m, 2H), 8.43 (m, 1H);

Elemental Analysis Found C, 60.0; H, 6.0; N, 12.3; C₂₈ H₃₃ N₅ O₄ S0.3CH₂ Cl₂ requires C, 60.4; H, 6.0; N, 12.4%.

The (3S)-3-(2-naphthalenesulphonamido)-3-(piperidinocarbonyl)propionicacid used as a starting material was obtained as follows:

N² -(tert-butoxycarbonyl)-L-aspartic acid O⁴ -benzyl ester (16.2 g) wasadded portionwise to a stirred mixture of 1,1'-carbonyldiimidazole (8.1g) in DMF (100 ml). The resultant mixture was stirred at ambienttemperature for 30 minutes. The mixture was cooled in an ice-bath andpiperidine (6 ml) was added dropwise. The mixture was stirred andallowed to warm to ambient temperature over 3 hours. The mixture waspartitioned between ethyl acetate and 2N aqueous hydrochloric acid. Theorganic phase was washed with water, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using ethyl acetate aseluent. There was thus obtained N² -(tert-butoxycarbonyl)-L-aspartic1-piperidide O⁴ -benzyl ester (17.9 g).

A portion (4.5 g) of the material so obtained was dissolved in ethylacetate (75 ml) and the solution was cooled in an ice-bath. Hydrogenchloride gas was led into the solution for 20 minutes. The mixture wasevaporated to give L-aspartic 1-piperidide O⁴ -benzyl esterhydrochloride salt (3.6 g);

NMR Spectrum (CDCl₃) 1.3-1.8 (m, 6H), 3.05-3.3 (m, 2H), 3.4-3.6 (m, 4H),4.9-5.0 (m, 1H), 5.15 (s, 2H), 7.3-7.4 (m, 5H), 8.5-8.8 (m, 3H).

A portion (2.63 g) of the material so obtained was reacted with2-naphthylsulphonyl chloride (2 g) using an analogous procedure to thatdescribed in Example 2. There was thus obtained benzyl(3S)-3-(2-naphthalenesulphonamido)-3-(piperidinocarbonyl)propionate asan oil (2.96 g, 82%).

A mixture of the material so obtained, 10% palladium-on-carbon catalyst(0.2 g) and ethanol (25 ml) was stirred under an atmosphere of hydrogenfor 6 hours. The mixture was filtered and the filtrate was evaporated.There was thus obtained(3S)-3-(2-naphthalenesulphonamido)-3-(piperidinocarbonyl)propionic acidas a foam (2.2 g, 86%);

NMR Spectrum (CDCl₃) 0.8-1.1 (m, 1H), 1.1-1.5 (m, 5H), 2.4-2.7 (m, 2H),3.0-3.4 (m, 4H), 4.7 (t, 1H), 5.3-5.7 (m, 2H), 7.5-7.7 (m, 2H), 7.75-8.0(m, 4H), 8.45 (s, 1H).

EXAMPLE 18

1,1'-Carbonyldiimidazole (0.307 g) was added to a solution of(3S)-3-[2-(2-naphthalenesulphonamido)acetamido]-3-(piperidinocarbonyl)propionicacid (0.85 g) in DMF (10 ml) and the mixture was stirred at ambienttemperature for 30 minutes. 1-(4-Pyridyl)piperazine (0.309 g) was addedand the mixture was stirred at ambient temperature for 16 hours. Themixture was partitioned between ethyl acetate and water. The organicphase was washed with water and with brine, dried (MgSO₄) andevaporated. The residue was purified by column chromatography usingincreasingly polar mixtures of methylene chloride and methanol aseluent. The material so obtained was recrystallised from acetonitrile.There was thus obtained2-(2-naphthalenesulphonamido)-N-{(1S)-1-(piperidinocarbonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]ethyl}-acetamide(0.201 g, 17%), m.p. 201-203° C.;

NMR Spectrum (CDCl₃ +CD₃ CO₂ D) 1.2-1.6 (m, 6H), 2.1-2.3 (m, 1H),2.7-2.9 (m, 1H), 3.1-4.8 (m, 14H), 4.9-5.0 (m, 1H), 7.0 (d, 2H),7.6-7.75 (m, 2H), 7.8-7.85 (m, 1H), 7.9-8.15 (m, 3H), 8.2-8.3 (m, 2H),8.4 (s, 1H);

Elemental Analysis Found C, 59.9; H, 6.2; N, 14.1; C₃₀ H₃₆ N₆ O₅ S 0.5H₂O requires C, 59.9; H, 6.2; N, 14.0%.

The(3S)-3-[2-(2-naphthalenesulphonamido)acetamido]-3-(piperidinocarbonyl)propionicacid used as a starting material was obtained as follows:1,1'-Carbonyldiimidazole (0.81 g) was added to a stirred mixture ofN-(2-naphthylsulphonyl)glycine (1.33 g) and DHF (10 ml) and the mixturewas stirred at ambient temperature for 30 minutes. L-Aspartic1-piperidide O⁴ -benzyl ester hydrochloride salt (1.63 g) andtriethylamine (0.87 ml) was added in turn and the mixture was stirred atambient temperature for 16 hours. The mixture was partitioned betweenethyl acetate and water. The organic phase was washed with water andwith brine, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography using a 3:2 mixture of methylene chloride andethyl acetate as eluent. There was thus obtained benzyl(3S)-3-[2-(2-naphthalenesulphonamido)acetamido]-3-(piperidinocarbonyl)propionateas a foam (1.59 g).

A mixture of a portion (1.44 g) of the material so obtained, 10%palladium-on-carbon catalyst (0.2 g) and ethanol (30 ml) was stirredunder an atmosphere of hydrogen for 6 hours. The mixture was filteredand the filtrate was evaporated. The residue was purified by columnchromatography using ethyl acetate as eluent. There was thus obtained(3S)-3-[2-(2-naphthalenesulphonamido)acetamido]-3-(piperidinocarbonyl)propionicacid as an oil (0.858 g);

NMR Spectrum (CDCl₃) 1.4-1.7 (m, 6H), 2.4-2.8 (m, 2H), 3.4-3.6 (m, 4H),3.6-3.8 (m, 2H), 5.1-5.35 (m, 1H), 6.5-6.6 (m, 2H), 7.5-7.7 (m, 2H),7.8-8.0 (m, 5H), 8.4 (s, 1H).

EXAMPLE 19

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with1-[3-amino-2-(benzyloxycarbonylamino)propionyl]piperidine to giveN-[2-(benzyloxycarbonylamino)-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)piperidine-4-carboxamidein 44% yield;

NMR Spectrum 1.5-2.0 (m, 10H), 2.2-2.4 (m, 1H), 2.8-3.0 (m, 2H),3.2-3.35 (m, 1H), 3.4-3.7 (m, 5H), 3.8-3.95 (m, 2H), 4.7-4.8 (m, 1H),5.2 (s, 2H), 6.0-6.2 m,1H), 6.2-6.4 (m, 1H), 6.6-6.7 (m, 2H), 7.3-7.4(m, 5H), 8.2-8.3 (m, 2H);

Elemental Analysis Found C, 63.1; H, 7.4; N, 13.3; C₂₇ H₃₄ N₅ O₄ HOrequires C, 63.4; H, 7.2; N, 13.7%.

EXAMPLE 20

A mixture of 3- (2-naphthalenesulphonamido)propionic acid [prepared bythe reaction of 2-naphthylsulphonyl chloride and 3-aminopropionic acid;0.163 g], N-hydroxysuccinimide (0.067 g),N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.112 g) and DMF (10 ml)was stirred at ambient temperature for 30 minutes. A solution ofN-[2-amino-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)piperidine-4-carboxamide(0.21 g) in DMF (2 ml) was added and the mixture was stirred at ambienttemperature for 16 hours. The mixture was evaporated and the residue waspartitioned between methylene chloride and water. The organic phase waswashed with 2N aqueous sodium hydroxide solution and with water, dried(MGSO and evaporated. The residue was purified by column chromatographyusing increasingly polar mixtures of ethyl acetate and methanol aseluent. There was thus obtained 3-(2-naphthalenesulphonamido)-N-{1-(piperidinocarbonyl)-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}propionamide(0.14 g), m.p. 201-203° C.;

NMR Spectrum (CD₃ SOCD₃) 1.2-1.6 (m, 10H), 2.1-2.3 (m, 3H), 2.6-2.8 (m,2H), 2.9 (t, 2H), 3.0-3.1 (m, 1H), 3.3-3.5 (m, 3H), 3.7-3.9 (m, 2H),4.7-4.8 (s , 1H), 6.6-6.7 (m, 2H), 7.5-7.7 (m, 3H), 7.7-7.8 (m, 2H),7.9-8.2 (m, 6H), 8.35 (m, 1H);

Elemental Analysis Found C, 61.2; H, 6.4; N, 12.8; C₃₂ H₄₀ N₆ O₅ S 0.5EtAc requires C, 61.4; H, 6.6; N, 12.7%.

TheN-[2-amino-2-(piperidinocarbonyl)ethyl-1-(4-pyridyl)piperidine-4-carboxamideused as a starting material was obtained as follows:

A mixture of N- [2- (benzyloxycarbonylamino)-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)piperidine-4-carboxamide(1.37 g), 10% palladium-on-carbon catalyst (0.2 g) and ethanol wasstirred under an atmosphere of hydrogen for 1 hour. The mixture wasfiltered and the filtrate was evaporated. There was thus obtained therequired starting material in 91% yield.

EXAMPLE 21

Using an analogous procedure to that described in Example 2,N-[2-amino-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)piperidine-4-carboxamidewas reacted with naphthalene-2-carbonyl chloride to giveN-{1-(piperidinocarbonyl)-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-ethyl}naphthalene-2-carboxamidein 85% yield;

NMR Spectrum (CDCl₃) 1.5-2.1 (m, 10H), 2.3-2.4 (m, 1H), 2.8-3.0 (m, 2H),3.4-4.0 (m, 8H), 5.15-5.25 (m, 1H), 6.6 (m, 1H), 6.85 (m, 1H), 7.5-7.7(m, 2H), 7.8-8.0 (m, 5H), 8.2 (d, 2H), 8.35 (s, 1H);

Elemental Analysis Found C, 67.6; H, 7.0; N, 13.0; C₃₀ H₃₅ N₅ O₃ H₂ Orequires C, 67.8; H, 7.0; N, 13.1%.

EXAMPLE 22

A solution of 4-tolyl isocyanate (0.133 g) in methylene chloride (5 ml)was added dropwise to a stirred solution ofN-[2-amino-2-(piperidinocarbonyl)ethyll-1-(4-pyridyl)piperidine-4-carboxamide(0.359 g) in methylene chloride (10 ml). The mixture was stirred atambient temperature for 2 hours. The precipitate was isolated andpurified by column chromatography using a 9:1 mixture of methylenechloride and methanol as eluent. There was thus obtainedN-{2-piperidinocarbonyl-2-[3-(4-tolyl)ureido]ethyl}1-(4-pyridyl)-piperidine-4-carboxamide(0.13 g), m.p. 252-253° C.;

NMR Spectrum (CD₃ SOCD₃) 1.4-1.8 (m, 10H), 2.2 (s, 3H), 2.25 (m, 1H),2.7-2.9 (m, 2H), 3.05-3.25 (m, 2H), 3.35-3.5 (m, 2H), 3.5-3.6 (m, 2H),3.75-4.0 (m, 2H), 4.8-5.0 (m, 1H), 6.3 (d, 1H), 6.7 (m, 2H), 7.0 (d,2H), 7.25 (d, 2H), 7.95 (m, 1H), 8.05-8.15 (m, 1H), 8.7 (s, 1H);

Elemental Analysis Found C, 65.8; H, 7.4; N, 16.9; C₂ H₃₆ N₆ O₃ requiresC, 65.8; H, 7.4; N, 17.1%.

EXAMPLE 23

Using an analogous procedure to that described in Example 2,2-amino-N-{1-piperidinocarbonyl-2-1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamidehydrochloride salt was reacted with 4-toluenesulphonyl chloride to giveN-{1-piperidinocarbonyl-2-1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}-2-(4-toluenesulphonamido)acetamidein 50% yield as a foam;

NMR Spectrum (CD₃ SOCD₃) 1.3-1.8 (m, 10H), 2.2-2.4 (m, 4H), 2.7-2.9 (m,2H), 3.0-3.2 (m, 1H), 3.3-3.6 (m, 12H), 3.8-4.0 (m, 2H), 4.8-4.95 (m,1H), 6.7-6.8 (m, 2H), 7.35 (d, 2H), 7.6-7.7 (m, 2H), 8.05-8.2 (m, 2H),8.25 (d, 2H).

The2-amino-N-{1-piperidinocarbonyl-2-(1-(4-pyridyl)-piperidin-4-ylcarbonylaminolethyl}acetamidehydrochloride salt used as a starting material was obtained as follows:

2-(tert-Butoxycarbonylamino)acetic acid N-hydroxysuccinimide ester[obtained by the reaction of that acid and e-hydroxysuccinimide in thepresence of dicyclohexyl-carbodiimide, 0.272 g] was added to a stirredsolution ofN-[2-amino-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)piperidine-4-carboxamide(0.359 g) in methylene chloride (5 ml). The mixture was stirred atambient temperature for 16 hours. The mixture was partitioned betweenmethylene chloride and 2N aqueous sodium hydroxide solution. The organicphase was washed with water, dried (MgSO₄) and evaporated. The materialso obtained was suspended in methylene chloride (25 ml) and hydrogenchloride gas was led into the solution for 5 minutes. A clear solutionwas obtained followed by the deposition of a precipitate. The mixturewas evaporated to give the required starting material.

EXAMPLE 24

1,1'-Carbonyldiimidazole (0.11 g) was added to a stirred solution of2-(² -naphthalenesulphonamido)acetic acid (0.182 g) in DMF (2 ml) whichhad been cooled to 5° C. The mixture was stirred at 5° C. for 30minutes. A solution of1-[4-amino-4-(piperidinocarbonyl)butyryl]-4-(4-pyridyl)piperazine (0.247g) in DMF (3 ml) was added and the mixture was stirred at ambienttemperature for 16 hours. The mixture was partitioned between ethylacetate and water. The organic phase was washed with water, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using a 95:5:0.5 mixture of ethyl acetate, methanol andaqueous ammonium hydroxide as eluent. There was thus obtained2-(2-naphthaleneulphonamido)-N-{1-piperidinocarbonyl-3-[4-(4-pyridyl)piperazin-1-ylcarbonyl]propyl}acetamide(0.14 g);

NMR Spectrum (CD₃ SOCD₃) 1.4-1.7 (m, 7H), 1.8-1.95 (m, 1H), 2.1-2.4 (m,2H), 3.2-3.6 (m, 14H), 4.65-5.75 (m, 1H), 6.8 (d, 2H), 7.6-7.75 (m, 2H),7.8-7.9 (m, 1H), 7.9-8.2 (m, 7H), 8.45 (s, 1H).

The 1-[4-amino-4-(piperidinocarbonyl)butyryl]-4-(4-pyridyl)piperazineused as a starting material was obtained as follows:

A solution of piperidine (0.85 g) in methylene chloride (5 ml) was addeddropwise to a solution of N² -benzyloxycarbonyl-DL-glutamic anhydride[J. Chem. Soc., 1950, 1954; 2.63 g] in methylene chloride (20 ml) whichhad been cooled to 0° C. The mixture was stirred at 0° C. for 1 hour.The mixture was extracted with ethyl acetate. The extract was acidifiedby the addition of concentrated hydrochloric acid, washed with water,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using increasingly polar mixtures of ethyl acetate,acetic acid and methanol as eluent (99:1:0 to 99:1:5). There was thusobtained N² -benzyloxycarbonyl-DL-glutamic C¹ -piperidide (0.78 g), m.p.92-93° C.

A portion (0.7 g) of the material so obtained was dissolved in DMF (10ml) and cooled in an ice-bath. 1,1'-Carbonyldiimidazole (0.325 g) wasadded and the mixture was stirred at 5° C. for 30 minutes. A solution of1-(4-pyridyl)piperazine (0.327 g) in DMF (2 ml) was added and themixture was stirred at ambient temperature for 3 hours. The mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with water, dried (MgSO₄) and evaporated. There was thus obtained1-[4-(benzyloxycarbonylamino)-4-(piperidinocarbonyl)-butyryl]-4-(4-pyridyl)piperazine(0.55 g).

A portion (0.4 g) of the material so obtained, 10% palladium-on-carboncatalyst (0.1 g) and ethanol (20 ml) was stirred under an atmosphere ofhydrogen for 6 hours. The mixture was filtered and the filtrate wasevaporated. There was thus obtained1-[4-amino-4-(piperidinocarbonyl)butyryl]-4-(4-pyridyl)piperazine (0.26g);

NMR Spectrum (CDCl₃ +CD₃ SOCD₃) 1.4-1.7 (m, 6H), 1.9-2.1 (m, 1H),2.3-2.6 (m, 2H), 2.7-2.8 (m, 1H), 3.2-3.8 (m, 12H), 6.65 (d, 2H), 8.3(d, 2H).

EXAMPLE 25

Using an analogous procedure to that described in Example 1,2-[4-(4-pyridyl)piperazin-1-yl]acetyl chloride was reacted withN-(3-aminopropyl)naphthalene-2-sulphonamide to giveN-[3-(2-naphthalenesulphonamido)propyl]-2-[4-(4-pyridyl)piperazin-1-yl]acetamidein 34% yield;

NMR Spectrum (CD₃ SOCD₃) 1.5-1.7 (m, 2H), 2.75-2.9 (t, 2H), 2.9-3.0 (s,2H), 3.1-3.25 (t, 2), 3.4-3.6 (m, 1H), 7.6-7.9 (1, 6H), 8.0-8.2 (m, 4H),8.4 (s, 1H), 8.7-8.8 (d, 2H);

Elemental Analysis Found C, 61.6; H, 6.25; N, 15.0; C₂₄ H₂₉ N₅ O₃ Srequires C, 61.2; H, 6.2; N, 14.8%.

The N-(3-aminopropyl)naphthalene-2-sulphonamide used as a startingmaterial was obtained by the reaction of 2-naphthylsulphonyl chloride (2g) and 1,3-diaminopropane (2.95 ml) in methylene chloride (25 ml)solution at ambient temperature for 16 hours.

EXAMPLE 26

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted withN-(piperidin-4-yl)naphthalene-2-sulphonamide hydrochloride salt to give4-(2-naphthalenesulphonamido)-1-[-1-(4-pyridyl)piperidin-4-ylcarbonyl]piperidinein 28% yield;

NNR Spectrum (CD₃ SOCD₃) 1.1-1.4 (m, 2H), 1.5-1.8 (m, 6H), 2.6-2.8 (m,1H), 2.85-3.3 (m, 6H), 3.7-3.9 (m, 1H), 4.0-4.2 (m, 4H), 6.9-7.1 (d,2H), 7.5-7.7 (m, 2H), 7.8-8.1 (d , 6H), 8.4 (s, 1H);

Elemental Analysis Found C, 62.7; H, 6.5; N, 11.0; C₂₆ H₃₀ N₄ O₃ S 0.5H₂O requires C, 64.1; H, 6.3; N, 11.4%.

The N-(piperidin-4-yl)naphthalene-2-sulphonamide hydrochloride salt usedas a starting material was obtained as follows:

A mixture of 4-amino-1-benzylpiperidine (1.8 ml), 2-naphthylsulphonylchloride (2 g), triethylamine (3.7 ml) and methylene chloride (25 ml)was stirred at ambient temperature for 16 hours. The mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with water, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using increasingly polar mixtures ofethyl acetate and methanol as eluent. There was thus obtainedN-(1-benzylpiperidin-4-yl)naphthalene-2-sulphonamide (2.98 g).

A mixture of a portion (0.5 g) of the material so obtained and methylenechloride (20 ml) was cooled in an ice-bath and 1-chloroethylchloroformate (0.2 ml) was added. The mixture was stirred overnight atambient temperature. The mixture was evaporated. The residue wasdissolved in methanol (5 ml) and the solution was heated to reflux for 3hours. The mixture was evaporated and the residue was purified by columnchromatography using increasingly polar mixtures of ethyl acetate andmethanol as eluent. There was thus obtainedN-(piperidin-4-yl)naphthalene-2-sulphonamide hydrochloride salt (0.2 g);

NMR Spectrum (CD₃ SOCD₃) 1.5-1.8 (m, 4H), 2.75-2.9 (m, 2H), 3.05-3.2 (m,2H), 3.25-3.4 (m, 1H), 7.6-7.7 (m, 2H), 7.8-7.9 (m, IH), 7.9-8.15 (m,3H), 8.4 (s, 1H).

EXAMPLE 27

Using an analogous procedure to that described in Example 2,3-amino-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]pyrrolidine hydrochloridesalt was reacted with 2-naphthylsulphonyl chloride to give3-(2-naphthalenesulphonamido)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]pyrrolidinein 37% yield;

NMR Spectrum (CD SOCD₃ +CD₃ CO₂ D) 1.5-2.0 (m, 6H), 2.75-2.9 (m, 1H),3.1-4.0 (m, 7H), 4.0-4.3 (m, 2H), 7.0-7.1 (m, 2H),,7.6-7.7 (m, 2H),7.9-8.0 (m, 1H), 8.0-8.2 (m, 5H), 8.5 (d, 1H);

Elemental Analysis Found C, 56.8; H, 5.5; N, 10.3; C₂₅ H₂₈ N₄ SO₃ 2H₂ O0.5CH₂ Cl₂ requires C, 56.4; H, 6.1; N, 10.3%.

The 3-amino-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]pyrrolidinehydrochloride salt used as a starting material was obtained as follows:

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with3-(tert-butoxycarbonylamino)pyrrolidine to give3-(tert-butoxycarbonylamino)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]pyrrolidinein 41% yield.

The material so obtained was treated with hydrogen chloride gas using ananalogous procedure to that disclosed in the last paragraph of theportion of Example 1 which is concerned with the preparation of startingmaterials. There was thus obtained3-amino-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]pyrrolidine hydrochloridesalt in quantitative yield;

NMR Spectrum (CD₃ SOCD₃) 1.5-1.8 (m, 2H), 1.75-2.4 (m, 4H), 2.8-3.0 (m,1H), 3.25-4.0 (m, 7H), 4.2-4.4 (d, 2H), 7.7 (d, 2H), 8.1-8.3 (d, 2H),8.5-8.7 (m, 2H).

EXAMPLE 28

The procedure described in Example 2 was repeated except that8-chloronaphth -2-ylsulphonyl chloride was used in place of2-naphthylsulphonyl chloride. There was thus obtained1-(8-chloronaphth-2-ylsulphonyl)-4-[-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 74% yield;

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D) 1.35-1.7 (m, 4H), 2.85-3.15 (m, 7H),3.5-3.7 (m, 4H), 3.95-4.1 (m, 2H), 7.0 (d, 2H), 7.75 (t, 1H), 7.85-7.95(m, 2H), 8.1-8.2 (m, 3H), 8.3 (d, 1H), 8.55 (s, 1H);

Elemental Analysis Found C, 59.4; H, 5.5; N, 10.9; C₂₅ H₂₇ ClN₄ O₃ S0.5H₂ O requires C, 59.1; H, 5.5; N, 11.0%.

EXAMPLE 29

Using an analogous procedure to that described in Example 2,2-naphthylsulphonyl chloride was reacted with3-ethoxycarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine togive2-ethoxycarbonyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 31% yield;

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.05 (t, 3H), 1.5-1.8 (m, 4H),2.9-3.25 (m, 5H), 3.35-3.5 (m, 2H), 3.7-4.15 (m, 7H), 5.5-5.7 (m, 2H),6.75-6.95 (m, 2H), 7.6-7.85 (m, 3H), 8.0-8.15 (m, 5H), 8.45 (d, 1H);

Elemental Analysis Found C, 60.4; H, 6.1; N, 10.1; C₂₈ H₃₂ N₄ O₅ S H₂ Orequires C, 60.6; H, 6.1; N, 10.1%.

The 3-ethoxycarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazineused as a starting material was obtained as follows:

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with ethyl1-benzylpiperazine-2-carboxylate (Helv. Chim. Acta, 1962, 45, 2383) togive1-benzyl-2-ethoxycarbonyl-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 67% yield.

A mixture of the material so obtained (0.667 g), trifluoroacetic acid (2ml), 10% palladium-on-carbon catalyst (0.15 g) and methanol (20 ml) wasstirred under 7 atmospheres pressure of hydrogen for 48 hours. Themixture was filtered and evaporated. The residue was partitioned betweenmethylene chloride and a saturated aqueous sodium bicarbonate solution.The organic phase was washed with water, dried (HgSO₄) and evaporated.The residue was triturated under diethyl ether to give the requiredstarting material in quantitative yield;

NMR Spectrum (CD₃ SOCD₃) 1.2-1.4 (m, 3H), 1.8-2.0 (m, 4H), 2.7-3.55 (m,8H), 3.6-3.85 (m, 2H), 3.9-4.05 (m, 2H), 4.15-4.3 (m, 2H), 6.75 (d, 2H),8.3 (d, 2H).

EXAMPLE 30

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride hydrochloride salt wasreacted with N-(2-aminoethyl)-2-(2-naphthalenesulphonamido)acetamidehydrochloride salt to give2-(2-naphthalenesulphonamido)-N-{2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamidein 49% yield, m.p. 107-109° C.;

NMR Spectrum (CD₃ SOCD₃) 1.4-1.6 (m, 4H), 2.2-2.4 (m, 1H), 2.7-2.9 (m,2H), 2.9-3.1 (m, 4H), 3.2-3.4 (m, 2H), 3.6-4.0 (m, 2H), 6.7-6.8 (d, 2H),7.6-8.2 (m, 11H), 8.4 (s, 1H);

Elemental Analysis Found C, 59.7; H, 5.9; N, 14.1; C₂₅ H₂₉ N₅ O₄ S 0.4H₂O requires C, 59.7; H, 5.9; N, 13.9%.

The N-(2-aminoethyl)-2-(2-naphthalenesulphonamido)acetamidehydrochloride salt used as a starting material was obtained as follows:

1,1'-Carbonyldiimidazole (1.62 g) was added to a stirred solution ofN-(2-naphthylsulphonyl)glycine (2.65 g) in DMF (20 ml) and the mixturewas stirred at ambient temperature for 20 minutes. The mixture wascooled to 5° C. and a solution of2-(N-tert-butoxycarbonylamino)ethylamine (1.6 g) in DHF (5 ml) wasadded. The mixture was stirred at ambient temperature for 2 hours. Themixture was evaporated and the residue was partitioned between ethylacetate and 1M aqueous citric acid solution. The organic phase waswashed with water, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using increasingly polar mixtures ofmethylene chloride and ethyl acetate as eluent. There was thus obtainedN-[2-(tert-butoxycarbonylamino)ethyl]-2-(2-naphthalenesulphonamido)acetamide(2.3 g), m.p. 150°-152° C.

A portion (2 g) of the material so obtained was suspended in ethylacetate and the mixture was cooled to 5° C. Hydrogen chloride gas wasled into the mixture for 10 minutes to give a clear solution followed bythe deposition of a precipitate. The solid was isolated, washed withdiethyl ether and dried. There was thus obtained the required startingmaterial (1.37 g);

NMR Spectrum (CD₃ SOCD₃) 2.7-2.9 (m, 2H), 3.15-3.3 (m, 2H), 3.4-3.5 (d,2H), 7.6-7.9 (m, 3H), 7.9-8.3 (m, 8H), 8.45 (d, 1H).

EXAMPLE 31

Using an analogous procedure to that described in Example 3,N-(2-aminoethyl)-2-(2-naphthalenesulphonamido)acetamide hydrochloridesalt, 1,1'-carbonyldiimidazole and 1-(4-pyridyl)piperazine were reactedto give2-(2-naphthalenesulphonamido)-N-{2-[4-(4-pyridyl)piperazin-1-ylcarbonylamino]ethyl}acetamidein 10% yield;

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D) 3.1-3.2 (m, 4H), 3.4-3.6 (m, 6H),3.6-3.7 (m, 4H), 7.1 (d, 2H), 7.6-7.75 (m, 2H), 7.8-7.9 (m, 1H),8.0-8.05 (m, 1H), 8.1-8.2 (m, 4H), 8.4 (s, 1H);

Elemental Analysis Found C, 56.4; H, 5.9; N, 15.5; C₂₄ H₂₈ N₆ O₄ S 0.5H₂O 0.5EtAc requires C, 56.8; H, 6.0; N, 15.3%.

EXAMPLE 32

Triethylamine (0.686 ml) was added to a stirred solution of4-chloropyrimidine hydrochloride (0.151 g),2-(2-naphthalenesulphonamido)-N-[2-(piperidin-4-ylcarbonylamino)ethyl]acetamidehydrochloride salt (0.453 g) and ethanol (10 ml) and the mixture wasstirred at ambient temperature for 4 days. The mixture was partitionedbetween ethyl acetate and water. The organic phase was washed withwater, dried (MgSO₄) and evaporated. The residue was recrystallised fromacetonitrile. There was thus obtained2-(2-naphthalenesulphonamido)-N-{2-[1-(4-pyrimidinyl)piperidin-4-ylcarbonylamino]ethyl}acetamide(0.08 g), m.p. 178-179° C.;

NMR Spectrum (CD₃ SOCD₃) 1.3-1.6 (m, 2H), 1.65-1.85 (m, 2H), 2.3-2.45(m, 1H), 2.8-3.05 (m, 6H), 3.4 (d, 2H), 4.3-4.5 (m, 2H), 6.8 (d, 1H),7.3-7.8 (m, 3H), 7.8-7.95 (m, 2H), 8.0 (m, 2H), 8.1-8.2 (m, 3H), 8.4-8.5(m, 2H);

Elemental Analysis Found C, 57.6; H, 5.7; N, 16.6; C₂₄ H₂₈ N₆ O₄ Srequires C, 58.0; H, 5.7; N, 16.9%.

The2-(2-naphthalenesulphonamido)-N-[2-(piperidin-4-ylcarbonylamino)ethyl]acetamideused as a starting material was obtained as follows:

N-Hydroxybenzotriazole (0.135 g) andN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.191 g) were added inturn to a stirred solution of1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.229 g) in DMF (10ml) which had been cooled to 0° C. The mixture was stirred at 0° C. for30 minutes. A solution ofN-(2-aminoethyl)-2-(2-naphthalenesulphonamido)acetamide hydrochloridesalt (0.343 g) in DMF (5 ml) was added, followed by triethylamine (0.101g). The resultant mixture was allowed to warm to ambient temperature andwas stirred for 3 hours. The mixture was partitioned between ethylacetate and water. The organic phase was washed in turn with 2N aqueoushydrochloric acid, a saturated aqueous sodium bicarbonate solution andbrine, dried (MgSO₄) and evaporated. There was thus obtainedN-{2-[l-(tert-butoxycarbonyl)piperidin-4-ylcarbonylamino]ethyl}-2-(2-naphthalenesulphonamido)acetamide(0.192 g), m.p. 176-178° C.

The tert-butoxycarbonyl group was removed using an analogous procedureto that described in the last paragraph of the portion of Example 30which is concerned with the preparation of starting materials. There wasthus obtained2-(2-naphthalenesulphonamido)-N-[2-(piperidin-4-ylcarbonylamino)ethyl]acetamidehydrochloride salt in 96% yield.

EXAMPLE 33

The procedure described in Example 32 was repeated except that2-amino-4-chloropyrimidine hydrochloride salt was used in place of4-chloropyrimidine hydrochloride salt. There was thus obtainedN-{2-[1-(2-aminopyrimidin-4-yl)piperidin-4-ylcarbonylamino]ethyl}-2-(2-naphthalenesulphonamido)acetamidein 53% yield, m.p. 197-199° C.;

NMR Spectrum (CD₃ SOCD) 1.3-1.55 (m, 2H), 1.6-1.8 (m, 2H), 2.2-2.4 (m,1H), 2.7-2.9 (m, 2H), 2.9-3.1 (m, 4H), 3.4 (s, 2H), 4.2-4.4 (m, 2H), 5.9(s, 2H), 6.0 (d, 1H), 7.6-7.8 (m, 4H), 7.8-7.95 (m, 2H), 7.95-8.2 (m,4H), 8.45 (s, 1H);

Elemental Analysis Found C, 55.9; H, 5.6; N, 19.1; C₂₄ H₂₉ N₇ O₄ Srequires C, 56.3; H, 5.7; N, 19.2%.

EXAMPLE 34

The procedure described in Example 32 was repeated except that2-amino-4-chloro-6-methylpyrimidine hydrochloride was used in place of4-chloropyrimidine hydrochloride and that the reaction mixture washeated to 80° C for 16 hours. There was thus obtainedN-{2-[1-(2-amino-6-methylpyrimidin-4-yl)piperidin-4-ylcarbonylamino]ethyl}-2-(2-naphthalenesulphonamido)acetamidein 38% yield, m.p. 225-226° C.;

NMR Spectrum 1.3-1.5 (m, 2H), 1.6-1.8 (m, 2H), 2.05 (s, 3H), 2.2-2.4 (m,1H), 2.7-2.9 (m, 2H), 2.95-3.1 (m, 4H), 3.45 (s, 2H), 4.2-4.4 (m, 2H),5.8 (s, 2H), 5.9 (s, 1H), 7.6-7.75 (m, 3H), 7.8-8.0 (m, 2H), 8.0-8.2 (m,4H), 8.45 (s, 1H);

Elemental Analysis Found C, 57.1; H, 6.0; N, 18.4; C₂₅ H₃₁ N₇ 0 ₄ Srequires C, 56.9; H, 5.9; N, 18.4%.

EXAMPLE 35

Using an analogous procedure to that described in Example 18, 4-[2-(2-naphthalenesulphonamido)acetamido] butyric acid was reacted with1-(4-pyridyl)piperazine to give2-(2-naphthalenesulphonamido)N-{3-[4-(4-pyridyl)piperazin-1-ylcarbonyl]propyl}acetamidein 21% yield as a foam;

NMR Spectrum (CD₃ SOCD₃) 1.45-1.65 (m, 2H), 2.3 (t, 2H), 2.9-3.1(m, 2H),3.2-3.4 (m, 4H), 3.5-3.65 (m, 4H), 6.8 (m, 2H), 7.6-7.75 (m, 4H),8.0-8.3 (m, 6H), 8.45 (s, 1H);

Elemental Analysis Found C, 57.7; H, 6.1; N, 12.7; C₂₅ H ₂₉ N₅ O₄ S H₂ O0.5EtAc requires C, 58.2; H, 6.3; N, 12.6%.

The 4- [2-(2-naphthalenesulphonamido)acetamido]butyric acid used as astarting material was obtained as follows:

Using an analogous procedure to that described in the first paragraph ofthe portion of Example 30 which is concerned with the preparation ofstarting materials, N-(2-naphthylsulphonyl)glycine was reacted withmethyl 4-aminobutyrate to give methyl 4-[2-(2-naphthalenesulphonamido)acetamido]butyrate in 56% yield.

The material so obtained was hydrolysed using an analogous procedure tothat described in Example 9. There was thus obtained the requiredstarting material in 79% yield, m.p. 187-189° C.;

NMR Spectrum (CD₃ SOCD₃ +CD 3CO₂ D) 1.5-1.7 (m, 2H), 2.15 (t, 2H), 3.0(t, 2H), 3.5 (s, 2H), 7.6-7.8 (m, 2H), 7.8-7.9 (m, 1H), 7.95-8.2 (m,3H), 8.5 (s, 1H).

EXAMPLE 36

N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide (0.21 g) was added to astirred mixture of N-(2-naphthylsulphonyl)glycine (0.265 g),1-(4-pyridyl)piperazine (0.169 g) and DMF (10 ml) which had been cooledto 5° C. The mixture was stirred at ambient temperature for 3 hours. Themixture was partitioned between ethyl acetate and water. The organicphase was washed with water, dried (MgSO₄) and evaporated. The residuewas purified by column chromatography using a 19:1 mixture of methylenechloride and methanol as eluent. There was thus obtainedN-[4-(4-pyridyl)piperazin- 1-ylcarbonylmethyl naphthalene-2-sulphonamide (0.126 g), m.p. 182-184° C.;

NMR Spectrum (CD₃ SOCD₃) 3.1-3.6 (m, 8H), 3.8-3.9 (m, 2H), 6.7-6.8 (m,2H), 7.6-7.75 (m, 2H), 7.75-7.9 (m, 2H), 8.0-8.2 (m, 5H), 8.45 (s, 1H);

Elemental Analysis Found C, 61.0; H, 5.3; N, 13.5; C₂₁ H₂₂ N₄ O₃ Srequires C, 61.4; H, 5.4; N, 13.5%.

EXAMPLE 37

Using an analogous procedure to that described in Example 36, 4-(²-naphthalenesulphonamido)butyric acid was reacted with 1-(⁴-pyridyl)piperazine to giveN-{3-[4-(4-pyridyl)piperazin-1-ylcarbonyl]propyl]naphthalene-2-sulphonamidein 15% yield as a foam;

NMR Spectrum (CD₃ SOCD₃) 1.7-1.9 (m, 2H), 2.3-2.4 (t, 2H), 2.95-3.05 (m,2H), 3.2-3.3 (m, 4H), 3.4-3.5 (m, 2H), 3.6-3.75 (m, 2H), 5.4-5.6 (d,1H), 6.5-6.6 (m, 2H), 7.5-7.65 (m, 2H), 7.75-8.0 (m, 4H), 8.2-8.3 (m,2H), 8.35 (s, 1H).

The 4-(2-naphthalenesulphonamido)butyric acid used as a startingmaterial was obtained as follows:

Using an analogous procedure to that described in Example 2,2-naphthylsulphonyl chloride was reacted with methyl 4-aminobutyrate togive methyl 4-(2-naphthalenesulphonamido)butyrate in 94% yield.

The material so obtained was hydrolysed using an analogous procedure tothat described in Example 9. There was thus obtained the requiredstarting material in 88% yield, m.p. 123-125° C.;

NMR Spectrum (CDCl₃) 1.7-1.9 (m, 2H), 2.35 (t, 2H), 2.9-3.1 (m, 2H),6.3-6.5 (m, 1H), 7.5-7.7 (m, 2H), 7.8-8.1 (m, 4H), 8.4 (s, 1H).

EXAMPLE 38

A solution of 5-(2-pyridyl)thien-2-ylsulphonyl chloride [Chem. Abs.,1983, 98, 215349; 0.162 g] in methylene chloride (5 ml) was added to astirred mixture of 1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine(0.314 g), triethylamine (0.9 ml) and methylene chloride (15 ml). Theresultant mixture was stirred at ambient termperature of 18 hours. Themixture was partitioned between methylene chloride and water. Theorganic phase was washed with water, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using increasingly polarmixtures of methylene chloride and methanol as eluent. There was thusobtained 1-[l-(⁴-pyridyl)piperidin-4-ylcarbonyl]-4-[5-(2-pyridyl)thien-2-ylsulphonyl]piperazine(0.231 g, 74%);

NMR Spectrum (CD₃ SOCD₃) 1.4-1.7 (m, 4H), 2.8-3.1 (m, 7H), 3.55-3.75 (m,4H), 3.85-3.95 (m, 2H), 6.8 (d, 2H), 7.35-7.45 (m, 1H), 7.65 (d, 1H),7.9-8.0 (m, 2H), 8.05-8.15 (m, 3H), 8.55-8.6 (m, 1H);

Elemental Analysis Found C, 57.2; H, 5.5; N, 13.9; C₂₄ H₂₇ N₅ O₃ S₂0.25H₂ O requires C, 57.4; H, 5.5; N, 14.0%.

EXAMPLE 39

Using an analogous procedure to that described in Example 2,1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine was reacted with theappropriate (E)-styrenesulphonyl chloride. There were thus obtained the(E)-styrenes disclosed in Table I, the structures of which wereconfirmed by NMR spectroscopy. Unless otherwise stated, the appropriate(E)-styrenesulphonyl chlorides were obtained from the correspondingstyrenes using an analogous procedure to that described in Note b. belowTable I.

                                      TABLE I                                     __________________________________________________________________________    1  STR2##                                                                        -                                                                             Example 39          m.p. Yield                                               Compound No. R (° C.) (%)                                            __________________________________________________________________________     1.sup.a     hydrogen  gum  27                                                   2.sup.b 4-chloro 172-173 32                                                   3.sup.c 4-methyl 223-226 42                                                   4.sup.d 2-methyl 148-149 37                                                   5.sup.e 4-fluoro 125-126 55                                                   6.sup.f 2-chloro foam 39                                                      7.sup.g 3-chloro foam 49                                                      8.sup.h 3,4-dichloro foam 33                                                  9.sup.i 4-bromo foam 54                                                      10.sup.j 4-trifluoromethyl foam 30                                          __________________________________________________________________________     Notes                                                                         .sup.a. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.45-1.8 (m, 4H), 2.95-3.25 (m, 7H), 3.5-3.75 (m, 4H), 4.12 (m, 2H), 7.05     (d, 2H), 7.38 (m, 5H), 7.75 (m, 2H), 8.2 (d, 2H).                             .sup.b. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.4-1.65 (m, 4H), 2.8-3.0 (m, 3H), 3.12 (m, 4H), 3.65 (m, 4H), 3.92 (m,       2H), 6.8 (d, 2H), 7.4 (d, 2H), 7.5 (d, 2H), 7.8 (d, 2H), 8.15 (d, 2H).        The 4chlorostyrenesulphonyl chloride used as a starting material was          obtained as follows: Sulphuryl chloride (1.37 ml) was added dropwise to       DMF (1.55 ml) which was stirred and cooled to a temperature in the range      to 5° C. The mixture was stirred at ambient temperature for 30         minutes. 4Chlorostyrene (1.2 ml) was added - #and the mixture was stirred     and heated to 90° C. for 3.5 hours. The mixture was cooled to          ambient temperature and poured onto a mixture (25 ml) of ice and water.       The precipitate so formed was isolated, washed with water and dried. Ther     was thus obtained 4chloro-β-styrenesulphonyl chloride (1.8 g); NMR       Spectrum (CD.sub.3 SOCD.sub.3) - #6.95 (s, 2H), 7.4 (d, 2H), 7.55 (d, 2H)     .sup.c. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.4-1.85 (m, 4H), 2.3 (s, 3H), 2.95-3.3 (m, 7H), 3.6 (m, 4H), 4.07 (m,        2H), 7.0 (m, 3H), 7.25 (m, 3H), 7.5 (d, 2H), 8.05 (d, 2H).                    .sup.d. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.45-1.75 (m, 4H), 2.4 (s, 3H), 2.85-3.25 (m, 7H), 3.55-3.75 (m, 4H), 3.9     (m, 2H), 6.8 (d, 2H), 7.1-7.4 (m, 4H), 7.68 (m, 2H), 8.15 (d, 2H).            .sup.e. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.45-1.75 (m, 4H), 2.85-3.0 (m, 3H), 3.05-3.2 (m, 4H), 3.5-3.75 (m, 4H),      3.92 (m, 2H), 6.85 (d, 2H), 7.2-7.5 (m, 4H), 7.85 (m, 2H), 8.15 (d, 2H).      .sup.f. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.45-1.75 (m, 4H), 2.85-2.95 (m, 3H), 3.05-3.25 (m, 4H), 3.55-3.75 (m,        4H), 3.92 (m, 2H), 6.8 (d, 2H), 7.4-7.7 (m, 5H), 8.0 (m, 1H), 8.1 (d, 2H)     .sup.g. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.45-1.75 (m, 4H), 2.85-3.0 (m, 3H), 3.0-3.2 (m, 4H), 3.55-3.75 (m, 4H),      3.92 (m, 2H), 6.8 (d, 2H), 7.4-7.5 (m, 4H), 7.72 (m, 1H), 7.93 (m, 1H),       8.15 (d, 2H).                                                                 .sup.h. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3 +     CD.sub.3 CO.sub.2 D) 1.5-1.9 (m, 4H), 3.0-3.3 (m, 7H), 3.55-3.75 (m, 4H),     4.15 (m, 2H), 7.1 (d, 2H), 7.4 (d, 2H), 7.7 (m, 2H), 8.1 (s, 1H), 8.15 (d     2H).                                                                          .sup.i. The product gave the following NHR signals (CD.sub.3 SOCD.sub.3 +     CD.sub.3 CO.sub.2 D) 1.55-1.85 (m, 4H), 3.0-3.35 (m, 7H), 3.6-3.75 (m,        4H), 4.17 (m, 2H), 7.1 (d, 2H), 7.15-7.5 (m, 2H), 7.65 (m, 4H), 8.15 (d,      2H).                                                                          .sup.j. The product gave the foliowing NMR signals (CD.sub.3 SOCD.sub.3 +     CD.sub.3 CO.sub.2 D) 1.5-1.85 (m, 4H), 3.0-3.3 (m, 7H), 3.55-3.75 (m, 4H)     4.15 (m, 2H), 7.1 (d, 2H), 7.5 (m, 2H), 7.8 (d, 2H), 7.95 (d; 2H), 8.15       (d, 2H).                                                                 

EXAMPLE 40

Using an analogous procedure to that described in Example 2,1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine was reacted with theappropriate 2-naphthalenesulphonyl chloride. There were thus obtainedthe compounds disclosed in Table II, the structures of which wereconfirmed by NMR spectroscopy. Unless otherwise stated, the appropriatenaphthylsulphonyl chlorides were obtained from the correspondingnaphthalenes using an analogous procedure to that described in Note c.below Table III in Example 41.

                                      TABLE II                                    __________________________________________________________________________    2  STR3##                                                                       Example 40        m.p.      Yield                                             Compound No. R (° C.) (%)                                            __________________________________________________________________________    1.sup.a    4-chloro 199-203   38                                                2.sup.b 7-chloro glass 18                                                     3.sup.c 7-ethoxy glass 13                                                     4.sup.d 6,7-dimethoxy glass 30                                                5.sup.e 6-chloro 115 (decomposes) 82                                          6.sup.f 6-bromo 142-145 81                                                    7.sup.g 6-methoxy gum 28                                                      8.sup.h 7-methoxy glass 29                                                    9.sup.i 6-fluoro 108-111 (decomposes) 73                                    __________________________________________________________________________     Notes                                                                         .sup.a. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.35-1.65 (m, 4H), 2.75-2.9 (m, 3H), 3.0-3.15 (m, 4H), 3.6 (m, 4H), 3.85      (m, 2H), 6.75 (d, 2H), 7.9 (m, 3H), 8.1 (d, 2H), 8.35 (t, 2H), 8.5 (s,        1H).                                                                          .sup.b. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.65 (m, 4H), 2.8-3.05 (m, 7H), 3.5-3.7 (m, 4H), 3.8-3.9 (m, 2H), 1.35-16     (m, 4H), 2.8-3.05 (m, 7H), 3.5-3.7 (m, 4H), 3.8-3.9 (m, 2H), 6.75 (d, 2H)     7.78 (m, 2H), 8.15 (m, 4H), 8.45 (d, 1H).                                     .sup.c. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.35-1.7 (m, 4H), 1.45 (t, 3H), 2.8-3.05 (m, 7H), 3.3 (m, 2H), 3.5-3.7 (m     4H), 3.83 (m, 2H), 4.2 (m, 2H), 6.85 (d, 2H), 7.35 (m, 1H), 7.58 (m, 2H),     7.95-8.15 (m, 4H), 8.3 (d, 1H).                                               .sup.d. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.35-1.65 (m, 4H), 2.75-3.0 (m, 7H), 3.5-3.7 (m, 4H), 3.85 (m, 2H), 3.95      (s, 6H), 6.75 (d, 2H), 7.5 (s, 1H), 7.6 (m, 2H), 7.95 (d, 1H), 8.1 (m,        2H), 8.25 (s, 1H).                                                            .sup.e. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3 +     CD.sub.3 CO.sub.2 D) 1.45-1.8 (m, 4H), 2.9-3.1 (m, 5H), 3.22 (m, 2H),         3.55-3.75 (m, 4H), 4.1 (m, 2H), 7.05 (d, 2H), 7.65-7.85 (m, 2H), 8.1-8.25     (m, 5H), 8.45 (s, 1H); and the following analytical data: Found C, 58.9;      H, 5.3; N, 10.9; C.sub.25 H.sub.27 ClN.sub.4 O.sub.3 S 0.2CH.sub.2            Cl.sub.2 requires C, 58.7; H, 5.3; N, 10.9%.                             

The 6-chloro-2-naphthylsulphonyl chloride used as a starting materialwas obtained as follows:

A solution of sodium nitrite (2.7 g) in water (5 ml) was added during 2hours to a stirred mixture of 6-amino-2-naphthalenesulphonic acid (8.8g), dilute aqueous hydrochloric acid (2.8% weight/volume, 20 ml) andwater (15 ml) which had been cooled to 0° C. The mixture was stirred at0° C. for 30 minutes and then poured onto a stirred suspension ofcuprous chloride (3.96 g) in dilute aqueous hydrochloric acid (2.8%, 20ml). The mixture was stored at ambient temperature for 18 hours. Themixture was evaporated to give 6-chloro-2-naphthalenesulphonic acidwhich was used without further purification.

The material was suspended in DMF (40 ml) and cooled to 5° C. Thionylchloride (8.6 ml) was added dropwise and the mixture was stirred at 5°C. for 3 hours. The mixture was poured onto ice and extracted withmethylene chloride. The organic solution was dried (MgSO₄) andevaporated. The residue was purified by column chromatography using a20:1 mixture of hexane and ethyl acetate as eluent. There was thusobtained 6-chloro-2-naphthylsulphonyl chloride (2.49 g);

NMR Spectrum (CD₃ SOCD₃) 7.45 (m, 1H), 7.8 (m, 1H), 7.85 (d, 1H), 8.05(m, 2H), 8.2 (s, 1H).

f. The product gave the following NMR signals (CD₃ SOCD₃) 1.35-1.65 (m,4H), 2.75-3.05 (m, 7H), 3.5-3.7 (m, 4H), 3.87 (m, 2H), 6.8 (d, 2H), 7.85(m, 2H), 8.05-8.25 (m, 4H), 8.4 (d, 1H), 8.5 (d, 1H).

The 6-bromo-2-naphthylsulphonyl chloride used as a starting material wasobtained in 22% yield from 6-amino-2-naphthalenesulphonic acid using ananalogous procedure to that described in Note e above except thathydrobromic acid and cuprous bromide were used in place of hydrochloricacid and cuprous chloride respectively. The material gave the followingNHR signals (CD₃ SOCD₃) 7.65 (m, 1H), 7.75-8.0 (m, 3H), 8.15-8.2 (m,2H).

g. The product gave the following NMR signals (CD₃ SOCD₃, 100° C.)1.48-1.73 (m, 4H), 2.75-3.02 (m, 3H), 3.06-3.11 (t, 4H), 3.56 (t, 4H),3.76 (t, 1H), 3.81 (t, 1H), 3.95 (s, 3H), 6.7 (d, 2H), 7.32 (m, 1H),7.44 (m, 1H), 7.71 (m, 1H), 8.03 (m, 2H), 8.12 (d, 2H), 8.31 (d, 1H).

The 6-methoxy-2-naphthylsulphonyl chloride used as a starting materialwas obtained as follows:

A mixture of sodium 6-hydroxy-2-naphthylsulphonate (5 g) and DMSO (100ml) was added to a stirred suspension of sodium hydride (60% dispersionin mineral oil, 1 g) in DMSO (20 ml) and the mixture was stirred atambient temperature for 30 minutes. The mixture was cooled to 10° C. andmethyl iodide (22 ml) was added dropwise. The mixture was allowed towarm to ambient temperature and was stirred for 2 hours. The mixture waspoured into acetone and the precipitate was isolated and washed in turnwith acetone and diethyl ether. There was thus obtained sodium6-methoxy-2-naphthylsulphonate (3.3 g).

Thionyl chloride (0.82 ml) was added to a stirred solution of a portion(0.96 g) of the material so obtained in DMF (10 ml). The mixture wasstirred at ambient temperature for 2 hours. The mixture was poured ontoice. The precipitate was isolated and dried. There was thus obtained6-methoxy-2-naphthylsulphonyl chloride (0.7 g) which was used withoutfurther purification.

h. The product gave the following NMR signals (CD₃ SOCD₃) 1.4-1.65 (m,4H), 2.75-3.0 (m, 7H), 3.5-3.7 (m, 4H), 3.88 (m, 2H), 6.75 (d, 2H),7.35-7.65 (m, 3H), 7.95-8.1 (m, 4H), 8.35 (s, 1H).

The 7-methoxy-2-naphthylsulphonyl chloride used as a starting materialwas obtained from sodium 7-hydroxy-2-naphthylsulphonate using analogousprocedures to those described in Note g above.

i. The product gave the following NMR signals (CD₃ SOCD₃ +CD₃ CO₂ D)1.45-1.8 (m, 4H), 2.9-3.1 (m, 5H), 3.22 (m, 2H), 3.55-3.75 (m, 4H), 4.12(m, 2H), 7.1 (d, 2H), 7.57 (m, 1H), 7.75-7.9 (m, 2H), 8.15 (m, 2H), 8.3(m, 1H), 8.5 (d, 1H).

The 6-fluoro-2-naphthylsulphonyl chloride used as a starting materialwas obtained as follows:

6-Amino-2-naphthalenesulphonic acid (5.41 g) was added portionwiseduring 10 minutes to a stirred suspension of nitrosoniumtetrafluoroborate (3;12 g) in methylene chloride (100 ml) which had beencooled to 5° C. The mixture was stirred at 5° C. for 2 hours and atambient temperature for 18 hours. The mixture was evaporated and1,2-dichlorobenzene (100 ml) was added to the residue. The mixture wasstirred and heated to 150° C. for 2 hours. The mixture was cooled to 5°C. and thionyl chloride (3.6 ml) and DMF (10 ml) were added. The mixturewas stirred at ambient temperature for 18 hours. The mixture waspartitioned between methylene chloride and water. The organic phase wasdried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 9:1 mixture of hexane and ethyl acetate aseluent. There was thus obtained 6-fluoro-2-naphthylsulphonyl chloride(1.53 g);

NMR Spectrum (CD₃ SOCD₃) 7.4 (m, 1H), 7.65-7.9 (m, 3H), 8.05 (m, 2H),8.2 (d, 1H).

EXAMPLE 41

Using an analogous procedure to that described in Example 2,1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine was reacted with theappropriate benzenesulphonyl chloride. There were thus obtained thecompounds disclosed in Table III, the structures of which were confirmedby NMR spectroscopy.

                  TABLE III                                                       ______________________________________                                        3  STR4##                                                                        -                                                                              Example 41                 m.p. Yield                                       Compound No. R (° C.) (%)                                            ______________________________________                                        1.sup.a      4-bromo       glass  67                                            2.sup.b 4-phenyl glass 64                                                     3.sup.c 4-(4-chlorophenyl) glass 61                                         ______________________________________                                         Notes                                                                         .sup.a. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.4-1.7 (m, 4H), 2.8-3.0 (m, 7H), 3.5-3.7 (m, 4H), 3.8-3.95 (m, 2H), 6.75     (d, 2H), 7.65 (d, 2H), 7.85 (d, 2H), 8.12 (broad s, 2H).                      .sup.b. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.35-1.37 (m, 4H), 2.8-3.0 (m, 7H), 3.5-3.7 (m, 4H), 3.88 (m, 2H), 6.8 (d     2H), 7.5 (m, 3H), 7.78 (m, 4H), 7.95 (d, 2H), 8.1 (d, 2H).                    .sup.c. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3 +     CD.sub.3 CO.sub.2 D) 1.55-1.8 (m, 4H), 2.8-3.05 (m, 3H), 3.15 (t, 4H), 3.     (t, 4H), 3.85 (m, 2H), 6.75 (d, 2H), 7.55 (d, 2H), 7.75 (d, 2H), 7.9 (d,      2H), 8.15 (d, 2H).                                                       

The 4'-chloro-4-biphenylylsulphonyl chloride used as a starting materialwas obtained as follows:

Chlorosulphonic acid (9 ml) was added dropwise to a stirred solution of4-chlorobiphenyl (21 g) in chloroform (200 ml) and the mixture wasstirred at ambient temperature for 30 minutes. The precipitate wasisolated and washed with chloroform (50 ml). There was thus obtained4'-chloro-4-biphenylylsulphonic acid (26.8 g).

Thionyl chloride (0.85 ml) was added dropwise to a stirred solution of4'-chloro-4-biphenylylsulphonic acid (1.7 g) in DMF (120 ml) which hadbeen cooled to 5° C. The mixture was stirred at ambient temperature for3 hours. The mixture was poured into water and the resultant precipitatewas isolated, dissolved in diethyl ether, dried (MgSO₄) and re-isolatedby evaporation of the solvent. There was thus obtained4'-chloro-4-biphenylylsulphonyl chloride (0.7 g) which was used withoutfurther purification.

EXAMPLE 42

Using an analogous procedure to that described in Example 2,1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine was reacted withdibenzofuran-3-sulphonyl chloride to give1-(dibenzofuran-3-ylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazineas a glassy solid in 75% yield;

NMR Spectrum (CD₃ SOCD₃) 1.35-1.75 (m, 4H), 2.8-3.1 (m, 7H), 3.6-3.8 (m,4H), 3.9-4.0 (m, 2H), 6.8 (d, 2H), 7.67 (m, 2H), 7.85-8.2 (m, 5H), 8.5(d, 1H) , 8.75 (d, 1H)

Elemental Analysis Found C, 62.8; H, 5.5; N, 10.8; C₂₇ H₂₈ N₄ O₄ S 0.5H₂O requires C, 63.1; H, 5.7; N, 10.9%.

EXAMPLE 43

A mixture of2-ethoxycarbonyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine,2N aqueous sodium hydroxide solution (0.37 ml) and methanol (4 ml) wasstirred at ambient temperature for 3 hours. The mixture was evaporated.The residue was dissolved in water (4 ml) and acidified by the additionof glacial acetic acid. The resultant precipitate was washed with water,dried and triturated under diethyl ether. There was thus obtained1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-piperazine-2-carboxylicacid (0.082 g), m.p. 188-193° C.;

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D) 1.45-1.8 (m, 4H), 2.9-3.4 (m, 5H),3.78 (m, 1H), 4.1 (m, 2H), 4.5 (m, 2H), 7.1 (d, 2H), 7.6-7.9 (m, 3H),8.0-8.2 (m, 5H), 8.45 (d, 1H);

Elemental Analysis Found C, 59.6; H, 5.7; N, 10.3; C₂₆ H₂₈ N₄ O₅ S0.75H₂ O requires C, 59.8; H, 5.7; N, 10.7%.

EXAMPLE 44

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with ethyl1-(2-naphthylsulphonyl)piperazine-3-carboxylate to give2-ethoxycarbonyl-4-(2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazineas a glassy solid in 9% yield;

NMR Spectrum (CD SOCD 1.3 (t, 3H), 1.65-2.1 (m, 4H), 2.5 (m, 2H), 2.78(m, 1H), 3.05 (m, 2H), 3.6-3.95 (m, 5H), 4.2 (m, 2H), 4.4 (m, 1H), 5.07(m, 1H), 5.3 (m, 1H), 6.65 (d, 2H), 7.7 (m, 3H), 7.98 (m, 3H), 8.2 (d,2H), 8.35 (d, 1H);

Elemental Analysis Found C, 62.3; H, 6.5; N, 10.8; C₂₈ H₃₂ N₄ O₅ Srequires C, 62.7; H, 6.1; N, 10.4%.

The ethyl 1-(2-naphthylsulphonyl)piperazine-3-carboxylate used as astarting material was prepared as follows:

Using an analogous procedure to that described in Example 2, ethyl1-benzylpiperazine-2-carboxylate was reacted with 2-naphthylsulphonylchloride to give ethyl1-benzyl-4-(2-naphthylsulphonyl)piperazine-2-carboxylate in 93% yield.

1-Chloroethyl chloroformate (1.5 ml) was added to a solution of ethyl1-benzyl-4-(2-naphthylsulphonyl)piperazine-2-carboxylate (2.44 g) in1,2-dichloroethane (50 ml) and the mixture was stirred and heated toreflux for 48 hours. The mixture was evaporated and the residue wastriturated under hexane. Methanol (50 ml) was added to the resultant gumand the mixture was heated to reflux for 2 hours. The mixture wasevaporated and the residue was partitioned between methylene chlorideand water. The organic phase was dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using increasingly polarmixtures of methylene chloride and methanol as eluent. There was thusobtained ethyl 1-(2-naphthylsulphonyl)piperazine-3-carboxylate as a gum(1.55 g);

NMR Spectrum (CDCl₃) 1.3 (t, 3H), 2.65-3.0 (m, 3H), 3.5 (m, 2H), 3.75(m, 1H), 4.2 (q, 2H), 7.7 (m, 3H), 7.98 (m, 3H), 8.35 (d, 1H).

EXAMPLE 45

Using an analogous procedure to that described in Example 14,1-(4-pyridyl)piperazine was reacted with1-(2-naphthylsulphonyl)piperidine-3-carboxylic acid to give1-[1-(2-naphthylsulphonyl)piperidin-3-ylcarbonyl]-4-(4-pyridyl)piperazineas a foam in 25% yield;

NHR Spectrum (CD₃ SOCD₃) 0.95-1.75 (m, 6H), 2.3-2.45 (m, 2H), 2.6 (m,1H), 3.5-3.75 (m, 8H), 7.05 (d, 2H), 7.6-7.75 (m, 3H), 8.1 (m, 5H), 8.4(s, 1H).

The 1-(2-naphthylsulphonyl)piperidine-3-carboxylic acid used as astarting material was obtained as follows:

Using an analogous procedure to that described in Example 2, ethylpiperidine-3-carboxylate was reacted with 2-naphthylsulphonyl chlorideto give ethyl 1-(2-naphthylsulphonyl)piperidine-3-carboxylate in 62%yield.

A mixture of the material so obtained (1.33 g), potassium hydroxide(0.43 g) and ethanol (17 ml) was stirred and heated to 80° C. for 4hours. The mixture was evaporated. The residue was dissolved in water (5ml) and the solution was acidified by the addition of 2N aqueoushydrochloric acid. The resultant precipitate was isolated, washed withwater and dried. There was thus obtained1-(2-naphthylsulphonyl)piperidine-3-carboxylic acid (0.81 g);

NMR Spectrum (CD₃ SOCD₃) 1.45-1.64 (m, 2H), 1.8-1.95 (m, 2H), 2.25 (m,1H), 2.5 (m, 2H), 3.58 (m, 2H), 7.72 (m, 3H), 8.15 (m, 3H), 8.45 (d,1H).

EXAMPLE 46

Using an analogous procedure to that described in Example 1 except thatDMF was used in place of methylene chloride as the reaction solvent,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with1-(2-naphthylmethyl)-2-oxopiperazine trifluoroacetate salt to give1-(2-naphthylmethyl)-2-oxo-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-piperazinein 18% yield;

NMR Spectrum (CD₃ SOCD₃) 1.45-1.75 (m, 4H), 2.85-3.05 (m, 3H), 3.3 (m,2H), 3.65-4.4 (m, 6H), 4.75 (s, 2H), 6.8 (d, 2H), 7.5 (m, 3H), 7.8 (s,1H), 7.9 (d, 2H), 8.1 (d, 2H);

Elemental Analysis Found C, 70.6; H, 6.7; N, 12.5; C₂₆ H₂₈ N₄ O₂ 0.8H₂ Orequires C, 70.5; H, 6.7; N, 12.6%.

The 1-(2-naphthylmethyl)-2-oxopiperazine trifluoroacetate salt used as astarting material was obtained as follows:

Di-tert-butyl pyrocarbonate (7.75 g) was added portionwise to a stirredmixture 2-oxopiperazine (3.23 g), potassium carbonate (4.46 g),tert-butanol (15 ml) and water (15 ml). The mixture was stirred atambient temperature for 2 hours. The mixture was extracted with ethylacetate. The organic phase was dried and evaporated. The residue wasrecrystallised from ethyl acetate. There was thus obtained4-tert-butoxycarbonyl-2-oxopiperazine (5.31 g), m.p. 157-159° C.

Sodium hydride (60% dispersion in mineral oil, 0.145 g) was addedportionwise to a stirred mixture of4-tert-butoxycarbonyl-2-oxopiperazine (0.5 g) and DMF (15 ml) which hadbeen cooled to 5° C. The mixture was stirred at that temperature for 1.5hours. A solution of 2-bromomethylnaphthalene (0.552 g) in DMF (3 ml)was added dropwise. The mixture was allowed to warm to ambienttemperature and was stirred for 18 hours. The mixture was partitionedbetween methylene chloride and water. The organic phase was dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using a 3:2 mixture of hexane and ethyl acetate aseluent. There was thus obtained4-tert-butoxycarbonyl-1-(2-naphthylmethyl)-2-oxopiperazine as a gum(0.41 g).

A mixture of the material so obtained, trifluoroacetic acid (1.5 ml) andmethylene chloride (10 ml) was stirred at ambient temperature for 18hours. Water (0.5 ml) was added and the mixture was evaporated. Therewas thus obtained 1-(2-naphthylmethyl)-2-oxopiperazine trifluoroacetatesalt (0.4 g) which was used without further purification;

NMR Spectrum (CD₃ SOCD₃) 3.4-3.5 (m, 4H), 3.9 (s, 2H), 4.8 (s, 2H),7.4-7.6 (m, 3H), 7.8-8.0 (m, 4H).

EXAMPLE 47

Using an analogous procedure to that described in Example 20,2-[2-(2-naphthalenesulphonamido)acetamidol-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionicacid was reacted with 4-methylpiperidine to giveN-{1-(4-methylpiperidin-1-ylcarbonyl)-2-[-(4-pyridyl)piperidin-4-ylcarbonylaminoethyl}-2-(2-naphthalenesulphonamido)acetamide in 22% yield.

EXAMPLE 48

Using an analogous procedure to that described in Example 20,2-[2-(2-naphthalenesulphonamido)acetamido]-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionicacid was reacted with morpholine to giveyl-morpholinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-ethyl}-2-(2-naphthalenesulphonamido)acetamidein 36% yield.

EXAMPLE 49

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with1-(2-naphthylsulphonyl)-1,4-diazepane to give1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]-1,4-diazepanein 42% yield, m.p. 178-180° C.;

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D) 1.5-2.0 (m, 6H), 3.15 (m, 1H),3.3-3.6 (m, 5H), 3.65 (m, 2H), 3.75 (m, 2H), 3.85 (m, 1H), 4.28 (m, 2H),7.25 (m, 1H), 7.75-8.0 (m, 3H), 8.15-8.4 (m, 5H), 8.6 (d, 1H);

Elemental Analysis Found C, 64.5; H, 6.2; N, 11.8; C₂₆ H₃₀ N₄ O₃ S0.25H₂ O requires C, 64.6; H, 6.3; N, 11.6%.

The 1-(2-naphthylsulphonyl)-1,4-diazepane used as a starting materialwas obtained as follows:

A solution of 2-naphthylsulphonyl chloride (2.26 g) in methylenechloride (5 ml) was added to a stirred solution of 1,4-diazepane(otherwise known as homopiperazine, 5 g) in methylene chloride (50 ml)which had been cooled to 5° C. The mixture was stirred at ambienttemperature for 2 hours. The mixture was partitioned between ethylacetate and 2N aqueous hydrochloric acid. The aqueous layer was basifiedto pH 13 by the addition of 10N aqueous sodium hydroxide solution andextracted with ethyl acetate. The organic phase was washed with water,dried (MgSO₄) and evaporated to give the required starting material in96% yield;

NMR Spectrum (CD₃ SOCD₃) 1.6-1.75 (m, 2H), 2.6-2.8 (m, 4H), 3.2-3.4 (m,4H), 7.6-7.9 (m, 3H), 8.0-8.3 (m, 3H), 8.5 (s, 1H).

EXAMPLE 50

A mixture of 1-(4-pyridyl)piperazine (0.136 g), 2,4,5-trichlorophenyl4-(2-naphthylsulphonyl)piperazine-1-carboxylate (0.2 g) and DMF (2 ml)was stirred and heated to 80° C. for 24 hours. The mixture was cooled toambient temperature and partitioned between ethyl acetate and water. Theorganic phase was washed with brine, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using a 19:1 mixture ofmethylene chloride and methanol as eluent. The oil so obtained wastriturated under diethyl ether. There was thus obtained1-(2-naphthylsulphonyl)-4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]piperazine(0.139 g, 73%), m.p. 210-212° C.;

NMR Spectrum (CD₃ SOCD₃) 2.9-3.05 (m, 4H), 3.1-3.4 (m, 12H), 6.7 (d,2H), 7.7 (m, 3H), 8.1-8.3 (m, 5H), 8.45 (s, 1H);

Elemental Analysis Found C, 61.4; H, 6.0; N, 14.7; C₂₄ H₂₇ N₅ O₃ Srequires C, 61.9; H, 5.9; N, 15.0%.

The 2,4,5-trichlorophenyl4-(2-naphthylsulphonyl)piperazine-1-carboxylate used as a startingmaterial was obtained as follows:

2,4,5-Trichlorophenyl chloroformate (0.26 g) was added dropwise to astirred mixture of 1-(2-naphthylsulphonyl)piperazine hydrochloride salt(0.63 g), triethylamine (0.41 g) and methylene chloride (10 ml). Themixture was stirred at ambient temperature for 18 hours. The mixture waspartitioned between ethyl acetate and 2N aqueous hydrochloric acid. Theorganic phase was washed with water and with brine, dried (MgSO₄) andevaporated. The residue was purified by column chromatography using a1:1 mixture of hexane and methylene chloride as eluent. There was thusobtained the required starting material (0.32 g);

NMR Spectrum (CD₃ SOCD₃) 3.0-3.2 (m, 4H), 3.5-3.8 (m, 4H), 7.65-7.8 (m,4H), 7.9 (s, 1H), 8.05 (m, 1H), 8.2 (m, 2H), 8.45 (s, 1H).

The 1-(2-naphthylsulphonyl)piperazine hydrochloride salt used as astarting material was obtained as follows:

A solution of 2-naphthylsulphonyl chloride (6.12 g) in methylenechloride (20 ml) was added dropwise to a stirred mixture of1-tert-butoxycarbonylpiperazine (5 g), triethylamine (5.63 ml) andmethylene chloride (50 ml) which had been cooled in an ice-bath. Themixture was stirred at 5° to 10° C. for 4 hours. The mixture waspartitioned between ethyl acetate and 1M aqueous citric acid solution.The organic phase was washed with water and with brine, dried (HgSO₄)and evaporated. There was thus obtained1-(tert-butoxycarbonyl)-4-(2-naphthylsulphonyl)piperazine as a solid(4.84 g), m.p. 174-176° C.

A portion (0.25 g) of the material so obtained as suspended in ethylacetate (20 ml) and the mixture was cooled in an ice-bath. Hydrogenchloride gas was led into the mixture for 20 minutes. The mixture wasevaporated. There was thus obtained 1-(2-naphthylsulphonyl)piperazinehydrochloride salt (0.21 g);

NMR Spectrum (CD SOCD ) 3.1-3.3 (m, 8H), 7.7-7.85 (m, 3H), 8.1 (d, 1H),8.15-8.2 (m, 2H), 8.5 (s, 1H), 9.2-9.4 (s, 1H).

EXAMPLE 51

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with(2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphonyl)piperazine to give(2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 13% yield;

NMR Spectrum (CDCl₃) 0.85-1.03 (m, 3H), 1.1-1.4 (m, 2H), 1.65-2.1 (m,4H), 2.65 (m, 1H), 2.90 (m, 2H), 3.18 (m, 1H), 3.58 (m, 2H), 3.89 (m,2H), 4.25 (m, 2H), 6.62 (d, 2H), 7.7 (m, 3H), 7.95 (m, 3H), 8.25 (d,2H), 8.39 (s, 1H);

Elemental Analysis Found C, 58.7; H, 6.2; N, 9.5; C₂₇ H₃₂ N₄ O₃ S 0.9CH₂Cl₂ requires C, 58.5; H, 6.0; N, 9.8%.

The (2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphonyl)piperazine used as astarting material was obtained in 50% yield by the reaction of(2RS,5SR)-2,5-dimethylpiperazine and 2-naphthylsulphonyl chloride usingan analogous procedure to that described in Example 2.

EXAMPLE 52

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with3-methyl-1-(2-naphthylsulphonyl)piperazine to give3-methyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 32% yield;

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.5-1.75 (m, 4H), 2.45-2.7 (m, 3H),3.19 (m, 1H), 3.57 (m, 1H), 3.75 (m, 3H), 4.06 (d, 1H), 4.52 (m, 1H),6.65 (d, 2H), 7.6-7.79 (m, 3H), 8.0-8.15 (m, 5H), 8.38 (s, 1H);

Elemental Analysis Found C, 64.1; H, 6.4; N, 11.3; C₂₆ H₃₀ N₄ O₃ S0.25EtOAc 0.15H₂ O requires C, 64.4; H, 6.47; N, 11.1%.

The 3-methyl-1-(2-naphthylsulphonyl)piperazine used as a startingmaterial was obtained in quantitative yield by the reaction of2-methylpiperazine and 2-naphthylsulphonyl chloride using an analogousprocedure to that described in Example 2.

EXAMPLE 53

Using an analogous procedure to that described in Example 2,3-methyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine was reactedwith 2-naphthylsulphonyl chloride. The reaction mixture was evaporatedand the residue was partitioned between ethyl acetate and 2N aqueoushydrochloric acid. The aqueous layer was basified to pH 14 by theaddition of 10N aqueous sodium hydroxide solution and extracted withethyl acetate. The organic phase was dried (MgSO₄) and evaporated. Therewas thus obtained2-methyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 96% yield;

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.5-1.75 (m, 4H), 2.75-3.3 (m, 6H),3.6-4.2 (m, 6H), 6.7 (d, 2H), 7.61-7.84 (m, 3H), 8.0-8.16 (m, 5H), 8.45(s, 1H);

Elemental Analysis Found C, 63.2; H, 6.5; N, 11.1; C₂₆ H₃₀ N₄ O₃ S 0.5H₂ O requires C, 63.2; H, 6.5; N, 11.3%.

The 3-methyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine used as astarting material was obtained in 39% yield by the reaction of1-(4-pyridyl)piperidine-4-carbonyl chloride and 2-methylpiperazine usingan analogous procedure to that described in Example 1

EXAMPLE 54

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with1-[(E)-4-chlorostyrylsulphonyl]-3-methylpiperazine. The reaction mixturewas evaporated and the residue was partitioned between ethyl acetate and2N aqueous hydrochloric acid. The aqueous layer was basified to pH 14 bythe addition of ION aqueous sodium hydroxide solution and extracted withethyl acetate. The organic phase was dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using increasingly polarmixtures of ethyl acetate and methanol as eluent. There was thusobtained4-[(E)-4-chlorostyrylsulphonyl]-2-methyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 24% yield;

NMR Spectrum (CD SOCD₃, 100° C.) 1.24 (d, 3H), 1.6-1.8 (m, 4H), 2.7 to3.05 (m, 5H), 3.22 (m, 1H), 3.45 (m, 1H), 3.62 (m, 1H), 3.84 (m, 2H),4.12 (m, 1H), 4.6 (m, 1H), 6.71 (d, 2H), 7.14 (d, 1H), 7.42 (d, 1H),7.4-7.7 (m, 4H), 8.15 (d, 2H);

Elemental Analysis Found C, 57.6; H, 6.2; N, 10.5; C₂₄ H₂₉ ClN₄ O₃0.5EtOAc 0.5H₂ O requires C, 57.6; H, 6.3; N, 10.3%.

The 1-[(E)-4-chlorostyrylsulphonyl]-3-methylpiperazine used as astarting material was obtained in 35% yield by the reaction of2-methylpiperazine and (E)-4-chlorostyrylsulphonyl chloride using ananalogous procedure to that described in Example 2.

EXAMPLE 55

A mixture of 4-chloropyrimidine hydrochloride (0.151 g),1-(2-naphthylsulphonyl)-4-(4-piperidinylcarbonyl)piperazine (0.387 g),triethylamine (0.202 g) and ethanol (5 ml) was stirred and heated toreflux for 1 hour. The mixture was evaporated and the residue waspurified by column chromatography using a 19:1 mixture of methylenechloride and methanol as eluent. The solid so obtained wasrecrystallised from acetonitrile. There was thus obtained1-(2-naphthylsulphonyl)-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]piperazine(0.135 g, 29%), m.p. 203-205° C.;

NMR Spectrum (CD ₃ SOCD ₃) 1.38 (m, 2H), 1.63 (m, 2H), 2.8-3.1 (m, 7H),3.5-3.8 (m, 4H), 4.3 (m, 2H), 6.75 (d, 1H), 7.7-7.85 (m, 3H), 8.05-8.3(m, 4H), 8.45 (m, 2H);

Elemental Analysis Found C, 61.4; H, 5.9; N, 15.1; C₂₄ H₂₇ N₅ O₃ S 0.2H₂O requires C, 61.5; H, 5.85; N, 14.9%.

The 1-(2-naphthylsulphonyl)-4-(4-piperidinylcarbonyl)piperazine used asa starting material was obtained as follows:

A solution of di-tert-butyl dicarbonate (10.9 g) in methylene chloride(50 ml) was added dropwise to a stirred mixture of ethylpiperidine-4-carboxylate (7.85 g), triethylamine (10.1 g) and methylenechloride (100 ml) which was cooled in an ice-bath to a temperature inthe range 5 to 10° C. The mixture was stirred at 5C for 1 hour. Themixture was evaporated and the residue was partitioned between diethylether and a 1M aqueous citric acid solution. The organic phase waswashed with water and with brine, dried (MgSO₄) and evaporated. Therewas thus obtained ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate asan oil.

A mixture of the material so obtained, 2N aqueous sodium hydroxidesolution (50 ml) and methanol (125 ml) was stirred at ambienttemperature for 1 hour. The mixture was concentrated by evaporation ofthe bulk of the methanol and the residue was partitioned between diethylether and 1M aqueous citric acid solution. The organic phase was washedwith water and with brine, dried (MgSO₄) and evaporated. There was thusobtained 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (10.6 g,92%).

N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide (2.5 g) was added to astirred mixture of 1-(2-naphthylsulphonyl)piperazine [3.61 g; obtainedby partitioning the corresponding piperazine hydrochloride salt betweendiethyl ether and 10N aqueous sodium hydroxide solution and drying(MgSO₄) and evaporating the organic phase],1-tert-butoxycarbonylpiperidine-4-carboxylic acid (3 g) and DMF (40 ml)which had been cooled in an ice-bath. The mixture was stirred at ambienttemperature for 18 hours. The mixture was partitioned between ethylacetate and water. The organic phase was washed with water and withbrine, dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using ethyl acetate as eluent. There was thus obtained1-(2-naphthylsulphonyl)-4-(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)piperazine (3.79 g,59%), m.p. 195-197° C.

A mixture of a portion (1 g) of the material so obtained andtrifluoroacetic acid (5 ml) was stirred at ambient temperature for 2hours. The mixture was partitioned between methylene chloride and 2Naqueous sodium hydroxide solution. The organic phase was washed withwater, dried (MgSO₄) and evaporated. There was thus obtained1-(2-naphthylsulphonyl)-4-(4-piperidinylcarbonyl)piperazine (0.61 g,77%);

NMR Spectrum (CD₃ SOCD₃) 1.2-1.5 (m, 4H), 2.4-2.7 (m, 3H), 2.8-3.1 (m,6H), 3.5-3.7 (m, 4H), 7.6-7.8 (m, 3H), 8.0-8.3 (m, 3H), 8.4 (s, 1H).

EXAMPLE 56

A mixture of 2-amino-4-chloro-6-methylpyrimidine (0.143 g),1-(2-naphthylsulphonyl)-4-(4-piperidinylcarbonyl)piperazine (0.387 g),triethylamine (0.101 g) and ethanol (5 ml) was stirred and heated toreflux for 18 hours. The mixture was cooled to ambient temperature andpartitioned between ethyl acetate and water. The organic phase waswashed with water, dried (MGSO₄) and evaporated. The residue wastriturated under diethyl ether. There was thus obtained4-[1-(2-amino-6-methylpyrimidin-4-yl)piperidin04-ylcarbonyl]-1-(2-naphthylsulphonyl)piperazine(0.29 g, 58%);

NMR Spectrum (CD₃ SOCD₃) 1.2-1.45 (m, 2H), 1.55 (m, 2H), 2.05 (s, 3H),2.8 (m, 3H), 2.9-3.2 (m, 4H), 3.5-3.7 (m, 4H), 4.23 (m, 2H), 5.95 (d,3H), 7.7-7.85 (m, 3H), 8.2 (m, 3H), 8.45 (s, 1H);

Elemental Analysis Found C, 60.1; H, 6.4; N, 16.6; C₂₅ H₃₀ N₆ O₃ S 0.3H₂O requires C, 60.1; H, 6.1; N, 16.8%.

EXAMPLE 57

A mixture of succinimido 1-(4-pyrimidinyl)piperidine-4-carboxylate(0.326 g), 1- [(E)-4-chlorostyrylsulphonyl]piperazine (0.4 g) and DMF (5ml) was stirred at ambient temperature for 16 hours. The mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with water, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using a 49:1 mixture of methylenechloride and methanol as eluent. The material so obtained wasrecrystallised from acetonitrile. There was thus obtained1-[(E)-4-chlorostyrylsulphonyl]-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]piperazine(0.133 g, 22%), m.p. 209-210° C.;

NMR Spectrum (CD₃ SOCD₃) 1.3-1.6 (m, 2H), 1.7 (m, 2H), 2.9-3.2 (m, 7H),3.5-3.8 (m, 4H), 4.4 (m, 2H), 6.8 (d, 1H), 7.4 (m, 4H), 7.8 (d, 2H),8.15 (d, 1H), 8.45 (s, 1H);

Elemental Analysis Found C, 55.2; H, 5.5; N, 14.7; C₂₂ H₂₆ ClN₅ O₃ Srequires C, 55.5; H, 5.5; N, 14.7%.

The succinimido 1-(4-pyrimidinyl)piperidine-4-carboxylate used as astarting material was obtained as follows:

Using an analogous procedure to that described in Example 32,4-chloropyrimidine hydrochloride was reacted with ethylpiperidine-4-carboxylate to give ethyl1-(4-pyrimidinyl)piperidine-4-carboxylate in 46% yield.

A mixture of the material so obtained (0.5 g), 2N aqueous hydrochloricacid (5 ml) and THF (15 ml) was stirred and heated to reflux for 18hours. The mixture was evaporated and the residue was washed with ethylacetate. There was thus obtained1-(4-pyrimidinyl)piperidine-4-carboxylic acid hydrochloride salt (0.49g, 95%);

NMR Spectrum (CD₃ SOCD₃) 1.6 (m, 2H), 2.0 (m, 2H), 2.7 (m, 1H), 3.4 (m,2H), 4.5 (broad s, 2H), 7.2 (d, 1H), 8.3 (d, 1H), 8.8 (s, 1H).

A mixture of the acid so obtained, N-hydroxysuccinimide (0.29 g),triethylamine (0.61 g), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide(0.48 g) and DMSO (10 ml) was stirred at ambient temperature for 5hours. The mixture was partitioned between ethyl acetate and water. Theorganic phase was washed with water, dried (MgSO₄) and evaporated. Therewas thus obtained succinimido 1-(4-pyrimidinyl)piperidine-4-carboxylatewhich was used without further purification.

The 1-[(E)-4-chlorostyrylsulphonyl]piperazine used as a startingmaterial was obtained in 42% yield by the reaction of piperazine and(E)-4-chlorostyrylsulphinyl chloride using an analogous procedure tothat described in Example 2.

EXAMPLE 58

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with1-(4'-methylbiphenyl-4-ylsulphonyl)piperazine to give1-(4'-methylbiphenyl-4-ylsulphonyl)-4-1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 67% yield, m.p.213-217° C.;

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D) 1.6-1.85 (m, 4H), 2.35 (s, 3H), 2.98(m, 1H), 3.05-3.3 (m, 6H), 3.55-3.65 (m, 4H), 3.95 (m, 2H), 6.95 (d,2H), 7.3 (d, 2H), 7.55 (d, 2H), 7.8 (m, 4H), 8.05 (d, 2H);

Elemental Analysis Found C, 65.0; H, 6.3; N, 10.8; C₂₈ H₃₂ N₄ O₃ S0.66H₂ O requires C, 65.1; H, 6.5; N, 10.8%.

The 1-(4'-methylbiphenyl-4-ylsulphonyl)piperazine used as a startingmaterial was prepared as follows:

A solution of 4-iodophenylsulphonyl chloride (5 g) in methylene chloride(i5O ml) was added dropwise to a stirred solution of piperazine (7.1 g)in methylene chloride (50 ml) which had been cooled in an ice bath. Themixture was stirred at ambient temperature for 14 hours. The mixture wasextracted with 2N aqueous hydrochloric acid. The aqueous solution waswashed with ethyl acetate, basified by the addition of 2N aqueous sodiumhydroxide solution and extracted with ethyl acetate. The organic extractwas washed with water, dried (MgSO₄) and evaporated. There was thusobtained 1-(4-iodophenylsulphonyl)piperazine (4.6 g) which was usedwithout further purification.

A mixture of the material so obtained (0.5 g), 4-tolylboronic acid (0.19g), 2M aqueous sodium carbonate solution (7.8 ml),tetrakis-(triphenylphosphine)palladium(O) (0.1 g), ethanol (15 ml) andtoluene (21 ml) was stirred and heated to reflux for 5 hours. Themixture was cooled to ambient temperature and partitioned between ethylacetate and water. The organic phase was washed with water, dried(MgSO₄) and evaporated. There was thus obtained1-(4'-methylbiphenyl-4-ylsulphonyl)piperazine (0.43 g);

NMR Spectrum (CD₃ SOCD₃) 2.35 (s, 3H), 2.7-2.9 (m, 8H), 7.35 (d, 2H),7.65 (d, 2H), 7.8 (d, 2H), 7.95 (d, 2H).

EXAMPLE 59

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with theappropriate 1-(phenylsulphonyl)piperazine. There were thus obtained thecompounds disclosed in Table IV, the structures of which were confirmedby NMR spectroscopy. Unless otherwise stated, the appropriate1-(phenylsulphonyl)piperazine was obtained from1-(4-iodophenylsulphonyl)piperazine using an analogous procedure to thatdescribed in the last paragraph of the portion of Example 58 which isconcerned with the preparation of starting materials.

                  TABLE IV                                                        ______________________________________                                        4  STR5##                                                                       Example 59                   m.p.   Yield                                     Compound No. R (° C.) (%)                                            ______________________________________                                         1.sup.a  4-(4-bromophenyl)                                                                              203-207  54                                           2.sup.b 4-(3,5-dichlorophenyl) gum 13                                         3.sup.c 3-(4-chlorophenyl) foam 12                                            4.sup.d 3-phenyl gum 12                                                       5.sup.e 4-iodo glass 79                                                       6.sup.f 4-(4-ethoxycarbonylphenyl) gum  5                                     7.sup.g 4-(4-cyanophenyl) gum  3                                              8.sup.h 3-(3,5-dichlorophenyl) gum 18                                         9.sup.i 4-(4-nitrophenyl) gum 27                                             10.sup.j 4-(4-chloro-2-nitrophenyl) gum 19                                  ______________________________________                                         Notes                                                                         .sup.a. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3 +     CD.sub.3 CO.sub.2 D) 1.6-1.85 (m, 4H), 2.98 (m, 1H), 3.05-3.3 (m, 6H),        3.55-3.65 (m, 4H), 3.93 (m, 2H), 6.9 (d, 2H), 7.55-7.65 (m, 4H), 7.8-7.9      (m, 4H), 8.1 (d, 2H).                                                         The 1(4'-bromobiphenyl-4-ylsulphonyl)piperazine used as a starting            material was obtained from 4bromobiphenyl. That compound was converted        into 4'-bromo4-biphenylylsulphonyl chloride using analogous - #procedures     to those described in Note c below Table III in Example 41. The material      so obtained was reacted with piperazine using an analogous procedure to       that described in Example 2. The required starting material gave the          following NMR signals (CD.sub.3 SDCD.sub.3) 2.7-2.8 (m, 4H), 2.8-2.9 (m,      4H), 7.75 (d, 4H), 7.8 (d, 2H), 7.95 (d, 2H).                                 .sup.b. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.5-1.75 (m, 4H), 2.8-3.15 (m, 7H), 3.55-3.65 (m, 4H), 3.8 (m, 2H), 6.7       (d, 2H), 7.55 (t, 1H), 7.7 (d, 2H), 7.8-7.95 (m, 4H), 8.1 (d, 2H).            The starting material 1(3',5'-dichlorobiphenyl-4-ylsulphonyl)piperazine       gave the following NMR signals (CD.sub.3 SOCD.sub.3) 2.7-2.8 (m, 4H),         2.8-2.9 (m, 4H), 7.65 (t, 1H), 7.75-7.85 (m, 4H), 8.0 (d, 2H).                .sup.c. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.55-1.75 (m, 4H), 2.7-3.05 (m, 3H), 3.05-3.15 (m, 4H), 3.55-3.6 (m, 4H),     3.6-3.75 (m, 2H), 6.7 (d, 2H), 7.5 (d, 2H), 7.65-7.8 (m, 4H), 7.92 (m,        2H), 8.1 (d, 2H).                                                             The starting material 1(4'-chlorobiphenyl-3-ylsulphonyl)-piperazine was       obtained by the reaction of 1(3-bromopheny1su1phony1)piperazine (obtained     by the reaction of piperazine and 3bromophenylsulphonyl chloride) and -       #4chlorophenylboronic acid using an analogous procedure to that described     in the last paragraph of the portion of Example 58 which is concerned wit     the preparation of starting materials. The required starting material gav     the following NMR signals (CD.sub.3 SOCD.sub.3) 2.7-2.8 (m, 4H), 2.8-2.9      (m, 4H), 7.6 (d, 2H), 7.7-7.8 (m, 5H), 8.05 (m, 1H).                          .sup.d. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.6-1.8 (m, 4H), 2.98 (m, 1H), 3.1-3.3 (m, 6H), 3.55-3.65 (m, 4H), 3.95       (m, 2H), 6.95 (d, 2H), 7.4-7.55 (m, 3H), 3.65-3.8 (m, 4H), 7.92 (m, 2H),      8.1 (d, 2H).                                                                  .sup.e. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.41-1.64 (m, 4H), 2.82-2.91 (m, 7H), 3.54-3.62 (m, 4H), 3.89 (d, 2H),        6.78 (d, 2H), 7.49 (d, 2H), 8.02 (d, 2H), 8.10 (d, 2H).                       .sup.f. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3)      1.28-1.68 (m, 7H), 2.76-3.07 (m, 7H), 3.49-3.75 (m, 4H), 3.8-4.07 (d, 2H)     4.42-4.43 (m, 2H), 6.76 (d, 2H), 7.8-8.2 (m, 10H).                            The starting material 1(4'-ethoxycarbonylbiphenyl-4-ylsulphonyl)piperazin     was obtained as follows:                                                      A mixture of 1(4-iodophenylsulphonyl)piperazine (5 g), bis(tributyltin)       (11 ml), tetrakis(triphenylphosphine)palladium(0) (0.16 g) and toluene -      #(200 ml) was stirred and heated to 120° C. for 36 hours. The          mixture was cooled to ambient temperature and filtered. The filtrate was      evaporated and the residue was purified by column chromatography using        increasingly polar mixtures of methylene chloride and methanol as eluent.     The material so obtained was dissolved in a mixture of methylene chloride     (20 ml), methanol (5 ml) and water (0.2 ml). Potassium fluoride (3 g) was     added and the mixture was stirred at - #ambient temperature for 1 hour.       The mixture was partitioned between methylene chloride and water. The         organic phase was washed with water, dried (MgSO.sub.4) and evaporated.       There was thus obtained [4(piperazin-1-ylsulphonyl)phenyl]tributyltin (1.     g).                                                                           A mixture of the material so obtained, ethyl 4iodobenzoate (1.6 g),           tetrakis(triphenylphosphine)palladium(0) (0.034 g) and toluene (50 ml) wa     stirred and heated to reflux for 72 hours. The mixture was - #evaporated      and the solid residue was washed with a 97:3 mixture of methylene chlorid     and methanol. There was thus obtained                                         1(4'-ethoxycarbonylbiphenyl-4-ylsu1phonyl)piperazine (0.76 g); NMR            Spectrum (CD.sub.3 SOCD.sub.3) 1.3-1.43 (t, 3H), 3.07-3.37 (d, 8H),           4.27-4.44 (m, 2H), 7.65-7.97 (m, 4H), 7.97-8.15 (m, 4H).                      .sup.g. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3,      100° C.) 1.57-1.78 (m, 4H), 2.79-3.08 (m, 3H), 3.08-3.18 (t, 4H),      3.55-3.68 (t, 4H), 3.75-3.82 (t, 1H), 3.85 (t, 1H), 6.74 (d, 2H),             7.85-8.02 (m, 8H), 8.14 (m, 2H).                                              The 1(4'-cyanobiphenyl-4-ylsulphonyl)piperazine used as a starting            material was obtained by the reaction of                                      [4(piperazin-1-ylsulphonyl)phenyl]tributyltin and 4iodobenzonitrile using     an - #analogous procedure to that described in Note f immediately above.      .sup.h. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3,      100° C.) 1.53-1.8 (m, 4H), 2.65-3.08 (m, 3H), 3.08-3.20 (t, 4H),       3.54-3.65 (t, 4H), 3.84 (t, 1H), 3.90 (t, 1H), 6.75-6.85 (d, 2H), 7.58 (t     1H), 7.7-7.9 .(m, 4H), 7.95-8.08 (m, 2H), 8.08-8.18 (m, 2H).                  The 1(3',5'-dichlorobiphenyl-3-ylsulphonyl)piperazine used as a starting      material was obtained as follows:                                             Using analogous procedures to those described in the portion of Example 5     which is concerned with the preparation of starting materials, piperazine     was reacted with 3bromophenylsulphonyl chloride to give                       1(3-bromophenylsulphonyl)piperazine which, in turn, was reacted with          3,5dichlorophenylboronic acid to give                                         1(3',5'-dichloro-biphenyl-3-ylsulphonyl)piperazine in 29% yield;              NMR Spectrum (CD.sub.3 SOCD.sub.3, 100° C.) 2.7-2.85 (m, 4H),          2.95-3.05 (m, 4H), 7.58 (t, 1H), 7.68-7.85 (m, 4H), 7.91-8.05 (m, 2H).        .sup.i. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3 ;     100° C.) 1.5-1.75 (m, 4H), 2.75-3.04 (m, SH), 3.05-3.17 (t, 4H),       3.53-3.65 (t, 4H), 3.75 (t, 1H), 3.81 (t, 1H), 6.69 (d, 2H), 7.88 (d, 2H)     7.93-8.04 (d, 4H), 8.1 (d, 2H), 8.3 (d, 2H).                                  The 1(4'-nitrobiphenyl-4-ylsulphonyl)piperazine used as a starting            material was obtained by the reaction of                                      [4(piperazin-1-ylsulphonyl)phenyl) tributyltin and 1iodo-4-nitrobenzene       using an analogous procedure to that described in Note f immediately          above.                                                                        .sup.j. The product gave the following NMR signals (CD.sub.3 SOCD.sub.3 ;     100° C.) 1.53-1.77 (m, 4H), 2.61-3.06 (m, 3H), 3.11 (t, 4H), 3.58      (t, 4H), 3.75 (t, 1H), 3.86 (t, 1H), 6.73 (d, 2H), 7.58 (d, 3H), 7.82 (m,     4H), 8.12 (d, 2H).                                                       

The 1-(4'-chloro-2'-nitrobiphenyl-4-ylsulphonyl)piperazine used as astarting material was obtained by the reaction of[4-(piperazin-1-ylsulphonyl)phenyl]tributyltin and2-bromo-5-chloro-1-nitrobenzene using an analogous procedure to thatdescribed in Note f immediately above.

EXAMPLE 60

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with1-[4-(2-pyridyl)phenylsulphonyl]piperazine to give1-[4-(2-pyridyl)phenyl-sulphonyl]-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 54% yield, m.p. 224-226° C.;

NMR Spectrum (CD₃ SOCD₃) 1.35-1.65 (m, 4H), 2.75-3.05 (m, 7H), 3.5-3.7(m, 4H), 3.88 (m, 2H), 6.75 (d, 2H), 7.45 (m, 1H), 7.8-8.0 (m, 3H),8.05-8.15 (m, 3H), 8.35 (d, 2H), 8.72 (m, 1H);

Elemental Analysis Found C, 62.7; H, 5.9; N, 14.0; C₂₆ H₂₉ N₅ O₃ S 0.5H₂O requires C, 62.4; H, 6.0; N, 14.0%.

The 1-[4-(2-pyridyl)phenylsulphonyl]piperazine used as a startingmaterial was obtained as follows:

A mixture of 1-(4-iodophenylsulphonyl)piperazine (0.48 g),(2-pyridyl)tributyltin (1.18 g),tetrakis(triphenylphosphine)palladium(O) (0.1 g) and toluene (15 ml) wasstirred and heated to reflux for 18 hours. The mixture was evaporatedand the residue was purified by column chromatography using increasinglypolar mixtures of methylene chloride and methanol as eluent. There wasthus obtained 1-[4-(2-pyridyl)phenylsulphonyl]piperazine (0.439 g);

NMR Spectrum (CD₃ SOCD₃) 2.65-2.8 (m, 4H), 2.8-2.9 (m, 4H), 7.45 (m,1H), 7.8-8.1 (m, 3H), 8.35 (d, 2H), 8.73 (m, 1H).

EXAMPLE 61

A mixture of2-ethoxycarbonyl-4-(2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine(0.67 g), 2N aqueous sodium hydroxide solution (2.5 ml) and methanol (10ml) was stirred at ambient temperature for 3 hours. The mixture wasevaporated and the residue was dissolved in water (10 ml). The solutionwas acidified by the addition of acetic acid. The precipitate wasisolated and dried. There was thus obtained2-carboxy-4-(2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine(0.47 g), m.p. 225-228° C. (decomposes);

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D, 100C) 1.55-1.9 (m, 4H), 2.45-2.55(m, 1H), 2.65-2.75 (m, 1H), 2.9-3.05 (m, 1H), 3.1-3.4 (m, 3H), 3.7 (m,1H), 3.92 (m, 2H), 4.07 (m, 1H), 4.25 (m, 1H), 4.98 (m, 1H), 6.9 (d,2H), 7.6-7.8 (m, 3H), 7.95-8.2 (m, 5H), 8.4 (d, 1H).

Elemental Analysis Found C, 58.4; H, 5.8; N, 10.3; C₂₆ H₂₈ N₄ O₅ S 1.5H₂O requires C, 58.3; H, 5.8; N, 10.45%.

EXAMPLE 62

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with ethyl1-(6-chloronaphth-2-ylsulphonyl)piperazine-3-carboxylate to give4-(6-chloronaphth-2-ylsulphonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazinein 37% yield;

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.2 (t, 3H), 1.5-1.8 (m, 4H), 2.6 (m,1H), 2.8 (m, 1H), 2.85-3.05 (m, 4H), 3.65-3.85 (m, 3H), 4.05-4.25 (m,4H), 5.1 (m, 1H), 6.7 (d, 2H), 7.65 (m, 1H), 7.8 (m, 1H), 8.1-8.25 (m,5H), 8.45 (d, 1H);

Elemental Analysis Found C, 58.5; H, 5.6; N, 9.6; C₂₈ H₃₁ ClN₄ O₅ Srequires C, 58.9; H, 5.5; N, 9.8%.

The ethyl 1-(6-chloronaphth-2-ylsulphonyl)piperazine-3-carboxylate usedas a starting material was obtained in 78% yield from ethyl1-benzylpiperazine-2-carboxylate and 6-chloronaphth-2-ylsulphonylchloride using analogous procedures to those described in the portion ofExample 44 which is concerned with the preparation of startingmaterials.

EXAMPLE 63

Using an analogous procedure to that described in Example 61,4-(6-chloronaphth-2-ylsulphonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinewas hydrolysed to give2-carboxy-4-(6-chloronaphth-2-ylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 90% yield, m.p. 215-220° C. (decomposes);

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.5-1.8 (m, 4H), 2.7-3.05 (m, 5H),3.6-3.85 (m, 4H), 4.1 (m, 1H), 4.25 (m, 1H), 4.95 (m, 1H), 6.7 (d, 2H),7.65 (m, 1H), 7.8 (m, 1H), 8.05-8.25 (m, 5H), 8.45 (d, 1H);

Elemental Analysis Found C, 56.7; H, 5.0; N, 9.9; C₂₆ H₂₇ ClN₄ O₅ S0.5H₂ O requires C, 56.6; H, 5.1; N, 10.15%.

EXAMPLE 64

A mixture of2-carboxy-4-(2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine(0.11 g), piperidine (0.064 ml), N-hydroxybenzotriazole (0.029 g),N,N-dicyclohexylcarbodiimide (0.054 g), DMF (2 ml) and DMSO (2 ml) wasstirred at ambient temperature for 18 hours. The mixture was partitionedbetween methylene chloride and water. The organic phase was dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using increasingly polar mixtures of methylene chlorideand methanol as eluent. There was thus obtained4-(2-naphthylsulphonyl)-2-piperidinocarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazineas a glass (0.063 g);

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D, 100° C) 1.2-1.8 (m, 10H), 2.7-3.05(m, 3H), 3.12 (m, 2H), 3.25-3.4 (m, 5H), 3.65 (m, 1H), 3.75-4.0 (m, 4H),5.2 (m, 1H), 6.85 (d, 2H), 7.6-7.75 (m, 3H), 7.95-8.1 (m, 5H), 8.35 (d,1H);

Elemental Analysis Found C, 63.6; H, 7.0; N, 12.0; C₃₁ H₃₇ N₅ O₄ S 0.5H₂O requires C, 63.7; H, 6.5; N, 12.0%.

EXAMPLE 65

A mixture of1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine-2-carboxylicacid (0.121 g) and thionyl chloride (0.2 ml) was stirred at ambienttemperature for 1 hour. The mixture was evaporated and methylenechloride (8 ml) and piperidine (0.23 ml) were added in turn to theresidue. The mixture was stirred at ambient temperature for 2 hours. Themixture was partitioned between methylene chloride and water. Theorganic phase was dried (MgSO₄) and evaporated. The residue was purifiedby column chromatography using increasingly polar mixtures of methylenechloride and methanol as eluent. There was thus obtained1-(2-naphthylsulphonyl) -2-piperidinocarbonyl-4- 1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine as a glass (0.061 g);

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D) 1.2-1.8 (m, 10H), 2.9-3.3 (m, 6H),3.45-3.75 (m, 4H), 3.9-4.2 (m, 4H), 4.47 (m, 1H), 5.0 (m, 1H), 6.8 (d,2H), 7.68 (m, 3H), 8.0-8.2 (m, 5H), 8.35 (d, 1H);

Elemental Analysis Found C, 62.5; H, 6.4; N, 11.7; C₃₁ H₃ N₅ O₄ S H₂ Orequires C, 62.7; H, 6.6; N, 11.8%.

EXAMPLE 66

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with2-benzyl-1-(2-naphthylsulphonyl)piperazine to give2-benzyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 70% yield; m.p. 186-188° C.;

NMR Spectrum (CD₃ SOCD₃) 1.6 (m, 4H), 2.7 (m, 3H), 3.0 (m, 4H), 3.9 (m,4H), 4.2 (d, 2H), 6.6 (d, 3H), 7.2 (d, 5H), 7.7 (m, 3H), 8.1 (m, 5H),8.5 (s, 1H).

Elemental Analysis Found C, 67.9; H, 6.3; N, 9.8; C₃₂ H₃₄ N₄ O₃ S 0.6H₂O requires C, 68.0; H, 6.3; N, 9.9%.

The 2-benzyl-1-(2-naphthylsulphonyl)piperazine used as a startingmaterial was obtained as follows:

N-Methylmorpholine (3.12 ml) was added to a stirred mixture ofN-tert-butoxycarbonyl-DL-phenylalanine (3 g), N-benzylglycine ethylester (2.18 g), N-hydroxybenzotriazole (1.26 g) and DMF (50 ml) whichhad been cooled to 0° C. The mixture was stirred at 0° C. for 30 minutesand at ambient temperature for 16 hours. The mixture was filtered andthe filtrate was evaporated. The residue was partitioned between ethylacetate and water. The organic phase was washed with water, dried(MgSO₄) and evaporated. The residue w as purified by columnchromatography using a 5:1 mixture of hexane and ethyl acetate as eluentto give a solid (3.7 g).

A mixture of the material so obtained and a 4H solution of hydrogenchloride in diethyl ether was stirred at ambient temperature for 16hours. The mixture was evaporated to give phenylalanyl-N-benzylglycineethyl ester (2.65 g);

NMR Spectrum (CD₃ SOCD₃) 1.2 (m, 2H), 3.1 (t, 2H), 3.6 (m, 4H), 4.1 (m,2H), 4.6 (m, 2H), 7.2 (m, 10H), 8.4 (s, 2H).

A mixture of a portion (0.5 g) of the material so obtained,N-methylmorpholine (0.15 g) and a 0.1M solution of acetic acid insec-butanol (25 ml) was stirred and heated to reflux for 3 hours. Themixture was evaporated and the residue was partitioned between methylenechloride and water. The organic phase was washed with water, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using increasingly polar mixtures of methylene chlorideand methanol as eluent. There was thus obtained1,3-dibenzyl-2,5-dioxopiperazine (0.29 g), m.p. 173-174° C.

After repetition of the previous reaction, a mixture of1,3-dibenzyl-2,5-dioxopiperazine (1.6 g), boron trifluoride diethylether complex (0.1 g) and THF (5 ml) was stirred and heated to refluxfor 15 minutes. The mixture was cooled to ambient temperature and boranedimethyl sulphide complex (0.04 ml) was added dropwise. The mixture wasstirred at ambient temperature for 30 minutes. The mixture wasevaporated and the residue was heated to 100° C. for 5 minutes. A 6Naqueous hydrochloric acid solution (1 ml) was added and the mixture washeated to reflux for 1 hour. The mixture was cooled to 0° C. and a 6Naqueous sodium hydroxide solution (1.5 ml) was added. The mixture waspartitioned between methylene chloride and a saturated aqueous potassiumcarbonate solution. The organic phase was washed with water, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography using increasingly polar mixtures of methylene chlorideand methanol as eluent. There was thus obtained 1,3-dibenzylpiperazine(0.29 g).

A solution of the material so obtained in methylene chloride (3 ml) wasadded dropwise to a stirred mixture of 2-naphthylsulphonyl chloride(0.257 g), triethylamine (0.7 ml) and methylene chloride (5 ml) whichhad been cooled to 0° C. The mixture was stirred at ambient temperaturefor 16 hours. The mixture was evaporated and the residue was partitionedbetween methylene chloride and water. The organic phase was washed withwater, dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using increasingly polar mixtures of methylene chlorideand methanol as eluent. There was thus obtained2,4-dibenzyl-1-(2-naphthylsulphonyl)piperazine (0.37 g);

NMR Spectrum (CD₃ SOCD₃) 1.8 (m, 2H), 2.6 (m, 3H), 3.1 (m, 2H), 3.45 (d,1H), 3.75 (d, 1H), 4.1 (s, 1H), 6.95 (m, 2H), 7.1 (m, 3H), 7.25 (s, 5H),7.75 (m, 3H), 8.1 (m, 3H), 8.5 (s, 1H).

A mixture of the material so obtained, 10% palladium-on-carbon catalyst(0.23 g) and methylene chloride (50 ml) was stirred under an atmosphereof hydrogen for 24 hours. The mixture was filtered and the filtrate wasevaporated. The residue was purified by column chromatography using a99:1 mixture of methylene chloride and methanol as eluent. There wasthus obtained 2-benzyl-1-(2-naphthylsulphonyl)piperazine (0.08 g).

NMR Spectrum (CD₃ SOCD₃) 2.4-2.8 (m, 4H), 3.1-3.4 (m, 3H), 3.6 (d, 1H),4.0 (t, 1H), 7.2 (m, 5H), 7.7 (m, 3H), 8.1 (m, 3H), 8.4 (s, 1H).

EXAMPLE 67

Using an analogous procedure to that described in Example 2,2-amino-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamidehydrochloride salt was reacted with (E)-4-chlorostyrylsulphonyl chlorideto give2-[(E)-4-chlorostyrylsulphonamido]-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-ethyl}acetamideas a gum (0.1 g, 16%);

NMR Spectrum (CDCl₃) 1.4-2.1 (m, 1OH), 2.45 (m, 1H), 2.6-3.1 (m, 2H),3.4-4.0 (m, 1OH), 5.1 (m, 1H), 6.7 (d, 2H), 6.85 (d, 1H), 6.95 (m, 1H),7.2-7.55 (m, 6H), 7.65 (d, 1H), 8.22 (m, 2H).

EXAMPLE 68

Using an analogous procedure to that described in Example 2,2-amino-N-{l-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamidehydrochloride salt was reacted with 3,4-dichlorophenylsulphonyl chlorideto give2-(3,4-dichlorophenylsulphonamido)-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamideas a gum (0.17 g, 27%);

NMR Spectrum (CD₃ SOCD₃) 1.4-1.8 (m, 1OH), 2.35 (m, 1H), 2.88 (m, 2H),3.02 (m, 1H), 3.15-3.5 (m, 8H), 3.55 (d, 1H), 3.9 (m, 2H), 4.85 (m, 1H),6.8 (d, 2H), 7.7-7.9 (m, 3H), 8.0 (d, 1H), 8.05 (d, 1H), 8.15 (m, 3H);

Elemental Analysis Found C, 49.9; H, 5.4; N, 12.5; C₂₇ H₃₄ Cl₂ N₆ O₅ S0.4CH₂ Cl₂ requires C, 49.9; H, 5.2; N, 12.7%.

EXAMPLE 69

Using an analogous procedure to that described in Example 56,4-chloropyrimidine was reacted with1-(6-chloronaphth-2-ylsulphonyl)-4-(4-piperidinylcarbonyl)piperazine.The precipitate which was deposited when the reaction mixture was cooledto ambient temperature was isolated and recrystallised fromacetonitrile. There was thus obtained1-(6-chloronaphth-2-ylsulphonyl)-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]piperazinein 60% yield, m.p. 218-219° C.;

NMR Spectrum (CD₃ SOCD₃) 1.25-1.5 (m, 2H), 1.62 (m, 2H), 2.8-3.1 (m,7H), 3.5-3.75 (m, 4H), 4.32 (m, 2H), 6.75 (m, 1H), 7.7 (m, 1H), 7.85 (m,1H), 8.15 (d, 1H), 8.2 (d, 1H), 8.28 (m, 3H), 8.45 (s, 1H), 8.5 (s, 1H);

Elemental Analysis Found C, 57.6; H, 5.3; N, 13.9; C₂₄ H₂₆ ClN₅ O₃ Srequires C, 57.7; H, 5.2; N, 14.0%.

The 1-(6-chloronaphth-2-ylsulphonyl)-4-(4-piperidinylcarbonyl)piperazineused as a starting material was obtained as follows:

Using analogous procedures to those described in two of the paragraphsof the portion of Example 50 which is concerned with the preparation ofstarting materials, 1-tert-butoxycarbonylpiperazine was reacted with6-chloronaphth-2-ylsulphonyl chloride to give 1-(⁶-chloronaphth-2-ylsulphonyl)piperazine hydrochloride salt in 58% yield.

The material so obtained was reacted with1-tert-butoxycarbonylpiperidine-4-carboxylic acid using analogousprocedures to those described in the third and fourth paragraphs of theportion of Example 55 which is concerned with the preparation ofstarting materials. There was thus obtained1-(6-chloronaphth-2-ylsulphonyl)-4-(4-piperidinylcarbonyl)piperazine in63% yield;

NMR Spectrum (CDCl₃) 1.5-1.75 (m, 4H), 2.4-2.7 (m, 3H), 3.0-3.2 (m, 6H),3.5-3.75 (m, 4H), 7.55 (m, 1H), 7.75 (m, 1H), 7.95 (m, 3H), 8.3 (s, 1H).

EXAMPLE 70

Using an analogous procedure to that described in Example 56,2-amino-4-chloropyrimidine was reacted with1-(6-chloronaphth-2-ylsulphonyl)-4-(4-piperidinylcarbonyl)piperazine.The precipitate which was deposited on cooling the reaction mixture wasisolated, washed with cold ethanol and dried. There was thus obtained4-[1-(2-aminopyrimidin-4-yl)piperidin-4-ylcarbonyl]-1-(6-chloronaphth-2-ylsulphonyl)piperazinein 73% yield, m.p. 265-267° C.;

NMR Spectrum (CD₃ SOCD₃) 1.0-1.4 (m, 4H), 2.5-2.7 (m, 3H), 2.7-2.9 (m,4H), 3.3-3.5 (m, 4H), 4.08 (m, 2H), 5.7 (s, 2H), 5.8 (d, 1H), 7.5-7.7(m, 3H), 7.75 (d, 1H), 8.05 (s, 1H), 8.1 (d, 1H), 8.3 (s, 1H);

Elemental Analysis Found C, 55.9; H, 5.4; N, 15.9; C₂₄ H₂₇ ClN₆ O₃ Srequires C, 56.0; H, 5.3; N, 16.3%.

EXAMPLE 71

Using an analogous procedure to that described in Example 32,3,4,5-trichloropyridazine was reacted with1-(6-chloronaphth-2-ylsulphonyl)-4-(4-piperidinylcarbonyl)piperazine.The crude reaction product was purified by column chromatography usingincreasingly polar mixtures of methylene chloride and ethyl acetate aseluent. There was thus obtained1-(6-chloronaphth-2-ylsulphonyl)-4-[1-(3,4-dichloropyridazin-5-yl)piperidin-4-ylcarbonyl]piperazinein 35% yield;

NMR Spectrum (CD₃ SOCD₃) 1.5-1.7 (m, 4H), 2.7-2.9 (m, 1H), 2.95-3.1 (m,6H), 3.5-3.85 (m, 6H), 7.7 (m, 1H), 7.85 (m, 1H), 8.15 (d, 1H), 8.22 (s,1H), 8.25 (d, 1H), 8.5 (s, 1H), 8.9 (s, 1H).

EXAMPLE 72

A mixture of1-(6-chloronaphth-2-ylsulphonyl)-4-[1-(3,4-dichloropyridazin-5-yl)piperidin-4-ylcarbonyl]piperazine(0.2 g), 10% palladium-on-carbon catalyst (0.05 g) and ethanol (10 ml)was stirred under an atmosphere of hydrogen gas for 48 hours. Themixture was filtered and the filtrate was evaporated. The residue waspurified by column chromatography using increasingly polar mixtures ofmethylene chloride and methanol as eluent. The re was thus obtained1-(6-chloronaphth-2-ylsulphonyl)-4-[1-(4-pyridazinyl)piperidin-4-ylcarbonyl]piperazine(0.045 g, 25%);

NMR Spectrum (CD₃ SOCD₃) 1.4-1.7 (m, 4H), 2.6-3.1 (m, 7H), 3.5-3.7 (m,4H), 3.9-4.0 (m, 2H), 6.85 (m, 1H), 7.7 (m, 1H), 7.82 (m, 1H), 8.15 (d,1H), 8.27 (m, 2H), 8.5 (s, 1H), 8.55 (d, 1H), 8.9 (d, 1H).

EXAMPLE 73

A mixture of1-(6-chloronaphth-2-ylsulphonyl)-4-(4-piperidinylcarbonyl)piperazine(0.96 g), triethylamine (0.35 ml) and methylene chloride (10 ml) wasadded dropwise to a stirred solution of 2,4,6-trichloro-1,3,5-triazine(0.42 g) in methylene chloride (20 ml) which had been cooled to 0° C.The mixture was stirred at 5° C. for 1 hour. The mixture was evaporatedand the residue was partitioned between ethyl acetate and water. Theorganic phase was washed with water, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using increasingly polarmixtures of methylene chloride and ethyl acetate as eluent. There wasthus obtained1-(6-chloronaphth-2-ylsulphonyl)-4-[1-(4,6-dichloro-1,3,5-triazin-2-yl)piperidin-4-ylcarbonyl]piperazine(0.96 g, 74%), m.p. 230-233° C.;

NMR Spectrum (CDCl₃) 1.7-1.9 (m, 4H), 2.7 (m, 1H), 3.0-3.2 (m, 6H),3.55-3.85 (m, 4H), 4.73 (m, 2H), 7.6 (m, 1H), 7.75 (m, 1H), 7.95 (m,3H), 8.3 (s, 1H);

Elemental Analysis Found C, 46.9; H, 3.9; N, 14.4; C₂₃ H₂₃ Cl₃ N₆ O₃ S0.25CH₂ Cl₂ requires C, 47.3; H, 4.0; N, 14.2%.

EXAMPLE 74

A mixture of 1-(4-pyridyl)piperazine (0.163 g), 4-nitrophenyl4-(6-chloronaphth-2-ylsulphonyl)piperazine-1-carboxylate (0.475 g) inDMF (5 ml) was stirred and heated to 100° C. for 16 hours. The mixturewas evaporated and the residue was partitioned between ethyl acetate and2N aqueous hydrochloric acid. The aqueous layer was basified by theaddition of dilute aqueous sodium hydroxide solution and the mixture wasextracted with ethyl acetate. The organic extract was dried (MgSO₄) andevaporated. The solid so obtained was recrystallised from a mixture ofisohexane and ethyl acetate. There was thus obtained1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]piperazine(0.34 g);

NMR Spectrum (CD₃ SOCD₃) 2.95-3.05 (m, 4H), 3.15-3.3 (m, 12H), 6.75 (m,2H), 7.75 (m, 1H), 7.8 (m, 1H), 8.1-8.3 (m, 5H), 8.5 (s, 1H);

Elemental Analysis Found C, 57.5; H, 5.3; N, 13.9; C₂₄ H₂₆ ClN₅ O₃ Srequires C, 57.7; H, 5.2; N, 14.0%.

The 4-nitrophenyl4-(6-chloronaphth-2-ylsulphonyl)piperazine-1-carboxylate used as astarting material was obtained as follows:

A solution of 4-nitrophenyl chloroformate (0.4 g) in methylene chloride(15 ml) was added to a stirred mixture of1-(6-chloronaphth-2-ylsulphonyl)piperazine hydrochloride salt (0.69 g),triethylamine (0.56 ml) and methylene chloride (30 ml) which had beencooled to 0° C. The mixture was stirred at ambient temperature for 16hours. The mixture was evaporated and the residue was partitionedbetween ethyl acetate and a concentrated aqueous sodium bicarbonatesolution. The organic solution was washed with 1N aqueous hydrochloricacid solution and with water, dried (MgSO₄) and evaporated. The solid soobtained was recrystallised from a mixture of isohexane and ethylacetate. There was thus obtained 4-nitrophenyl4-(6-chloronaphth-2-ylsulphonyl)piperazine-1-carboxylate (0.73 g);

NMR Spectrum (CD₃ SOCD₃) 3.1 (m, 4H), 3.5-3.75 (m, 4H), 7.25 (m, 1H),7.38 (d, 2H), 7.85 (m, 1H), 8.15-8.3 (m, 5H), 8.5 (s, 1H).

EXAMPLE 75

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with4-(2-naphthylsulphonyl)piperidine to give4-(2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperidinein 33% yield;

NMR Spectrum (CD₃ SOCD₃) 1.42-1.82 (m, 6H), 1.85-2.21 (m, 2H), 2.82-3.04(m, 4H), 3.73-3.98 (m, 5H), 4.43 (m, 1H), 6.78 (d, 2H), 7.64-7.89 (m,3H), 8.04-8.27 (m, 5H), 8.37 (s, 1H).

The 4-(2-naphthylsulphonyl)piperidine used as a starting material wasobtained as follows:

Triethylamine (8.8 ml) was added to a stirred mixture of tert-butyl4-hydroxypiperidine-1-carboxylate (European Patent Application No. 0 495750, Chem. Abstracts, Vol. 117, Abstract 191869g, 6.38 g),methanesulphonyl chloride (3.7 ml) and methylene chloride (70 ml) whichhad been cooled to 0° C. The mixture was stirred at 0° C. for 2 hoursand then evaporated. The residue was partitioned between ethyl acetateand a concentrated aqueous citric acid solution. The organic phase waswashed with water, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using ethyl acetate as eluent to givetert-butyl 4-mesyloxypiperidine-1-carboxylate (7.82 g).

A mixture of a portion (0.99 g) of the material so obtained, sodium2-naphthalenesulphinate (14.3 g) and DMF (70 ml) was stirred and heatedto 120° C. for 5 hours. The mixture was evaporated and the residue waspartitioned between ethyl acetate and 2N aqueous sodium hydroxidesolution. The organic phase was dried (MgSO₄) and evaporated to givetert-butyl 4-(2-naphthylsulphonyl)piperidine-1-carboxylate (0.64 g)which was used without further purification.

A mixture of a portion (0.56 g) of the material so obtained andtrifluoroacetic acid (5 ml) was stirred at ambient temperature for 1hour. The mixture was diluted with ethyl acetate and washed with 2Naqueous sodium hydroxide. The organic layer was dried (HgSO₄) andevaporated to give 4-(2-naphthylsulphonyl)piperidine (0.18 g);

NMR Spectrum (CD₃ SOCD₃) 1.36-2.08 (m, 4H), 2.8-3.05 (m, 4H), 4.12-4.55(m, 1H), 7.6-8.25 (m, 6H), 8.34 (s, 1H).

The sodium 2-naphthalenesulphinate used above was obtained as follows:

2-Naphthalenesulphonyl chloride (15.9 g) was added portionwise during 2hours to a stirred mixture of sodium sulphite (33 g), sodium bicarbonate(11.6 g) and water (66 ml) which had been warmed to 70° C. The resultantmixture was stirred at 75° C. for 1 hour and stored at ambienttemperature for 16 hours. The precipitate was isolated. There was thusobtained sodium 2-naphthalenesulphinate (31 g).

EXAMPLE 76

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with4-(2-naphthylthio)piperidine to give4-(2-naphthylthio)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperidine in62% yield;

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.25-1.75 (m, 6H), 1.87-2.1 (broad s,2H), 2.78-3.0 (m, 4H), 3.20 (d, 1H), 3.64 (m, 1H), 3.6-4.04 (m, 3H), 4.2(d, 1H), 6.78 (d, 2H), 7.44-7.58 (m, 3H), 7.63-7.74 (m, 3H), 7.75 (d,1H), 8.12 (s, 2H);

Elemental Analysis Found C, 72.2; H, 6.7; N, 9.7; C₂₆ H₂₉ N₃ OS requiresC, 72.4; H, 6.8; N, 9.7%.

The 4-(2-naphthylthio)piperidine used as a starting material wasobtained as follows:

A solution of 2-naphthalenethiol (2.34 g) in DMF (10 ml) was addeddropwise to a stirred mixture of sodium hydride (60% dispersion inmineral oil, 0.65 g) and DMF (20 ml) which had been cooled to 10° C. Theresultant mixture was stirred at 0° C. for 30 minutes. A solution oftert-butyl 4-mesyloxypiperidine-1-carboxylate (3.9 g) in DMF (40 ml) wasadded dropwise. The mixture was allowed to warm to ambient temperature.The mixture was partitioned between ethyl acetate and water. The organicphase was washed with water, dried (HgSO₄) and evaporated. The residuewas purified by column chromatography using methylene chloride aseluent. There was thus obtained tert-butyl4-(2-naphthylthio)piperidine-1-carboxylate (0.65 g).

A mixture of the material so obtained and trifluoroacetic acid wasstirred at ambient temperature for 30 minutes. The mixture was dilutedwith ethyl acetate and washed with 2N aqueous sodium hydroxide solution.The organic solution was dried (NgSO₄) and evaporated. There was thusobtained 4-(2-naphthylthio)piperidine (0.32 g);

NMR Spectrum (CD₃ SOCD₃) 1.42 (m, 2H), 1.88 (m, 2H), 2.58 (m, 2H), 2.94(m, 2H), 3.43 (m, 1H), 7.5 (m, 3H), 7.89 (m, 4H).

EXAMPLE 77

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with2-hydroxymethyl-4-(2-naphthylsulphonyl)piperazine to give2-hydroxymethyl-4-(2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 42% yield;

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.55-1.72 (m, 2H), 1.83-1.95 (m, 2H),2.35-3.05 (m, 8H), 3 .49 (m, 2H), 3.7 (m, 2H), 4.01 (m, 2H), 6.72 (d,2H), 7.63-7.79 (m, 3H), 8.0-8.2 (m, 5H), 8.39 (s, 1H);

Elemental Analysis Found C, 61.2; H, 6.2; N, 10.4; C₂₆ H₃₀ N₄ O₄ S0.25EtAC 0.75H₂ O requires C, 61.2; H, 6.4; N, 10.6%.

The 2-hydroxymethyl-4-(2-naphthylsulphonyl)piperazine used as a startingmaterial was obtained in 49% yield by the reaction of2-hydroxymethylpiperazine (J. Med. Chem., 1990, 33, 142) and2-naphthylsulphonyl chloride using an analogous procedure to thatdescribed in Example 2;

NMR Spectrum (CD₃ SOCD₃) 1.93 (t, 1H), 2.24 (m, 2H), 2.68 (m, 2H), 2.93(m, 1H), 3.6 (m, 2H), 4.67 (t, 1H), 7.76 (m, 3H), 8.07-8.28 (m, 3H),8.44 (s, 1H).

EXAMPLE 78

1,1'-Carbonyldiimidazole (0.208 g) was added to a stirred solution ofN-(6-chloronaphth-2-ylsulphonyl)glycine (0.39 g) in DHF (10 ml) and themixture was stirred at ambient temperature for 30 minutes.1-(4-Pyridyl)piperazine (0.21 g) was added and the mixture was stirredat ambient temperature for 18 hours. The mixture was partitioned betweenethyl acetate and water. The organic phase was washed with brine, dried(MgSO₄ ) and evaporated. The residue was recrystallised from a mixtureof hexane, ethyl acetate and methanol. There was thus obtained 1-[2-(6-chloronaphthalenesulphonamido)acetyl]-4-(4-pyridyl)piperazine (0.179g, 20%), m.p. 192-193° C.;

NMR Spectrum (CD₃ SOCD₃) 3.15 (m, 2H), 3.3-3.6 (m, 6H), 3.85 (m, 2H),6.7-7.0 (m, 2H), 7.6 (m, 1H), 7.8-8.0 (m, 2H), 8.1-8.3 (m, 4H), 8.5 (s,1H);

Elemental Analysis Found C, 56.5; H, 4.8; N, 12.4; C₂₁ H₂₁ ClN₄ O₃ Srequires C, 56.7; H, 4.8; N, 12.6%.

The N-(6-chloronaphth-2-ylsulphonyl)glycine used as a starting materialwas obtained as follows:

Triethylamine (0.278 ml) was added to a stirred mixture of6-chloronaphth-2-ylsulphonyl chloride (0.522 g), glycine methyl esterhydrochloride (0.251 g) and methylene chloride (10 ml) and the mixturewas stirred at ambient temperature for 1 hour. The mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with brine, dried (MgSO₄) and evaporated. The residue wasrecrystallised from methanol to give methylN-(6-chloronaphth-2-ylsulphonyl)glycine (0.46 g).

A mixture of the material so obtained, and 2N aqueous sodium hydroxidesolution (3 ml) was stirred at ambient temperature for 30 minutes. Themixture was partitioned between diethyl ether and water. The aqueousphase was acidified by the addition of 2N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was washed with waterand with brine, dried (HgSO₄) and evaporated. There was thus obtainedthe required starting material (0.39 g) which was used without furtherpurification.

EXAMPLE 79

A mixture of1-(4'-ethoxycarbonylbiphenyl-4-ylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine(0.08 g), 2N aqueous sodium hydroxide solution (0.28 ml), water (2 ml)and methanol (10 ml) was stirred and heated to reflux for 3 hours. Themixture was poured into water and extracted with methylene chloride. Theaqueous suspension was filtered. The solid so obtained was resuspendedin water. The mixture was acidified by the addition of glacial aceticacid and stirred for 2 hours. The solid was isolated, washed with waterand with diethyl ether and dried. There was thus obtained1-(4'-carboxybiphenyl-4-ylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine(0.035 g);

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.6-1.86 (m, 4H), 3.0 (m, 1H), 3.15(t, 4H), 3.32 (m, 2H), 3.63 (t, 4H), 3.97 (t, 1H), 4.03 (t, 1H), 7.01(d, 2H), 7.24-7.96 (m, 6H), 8.09 (d, 4H).

EXAMPLE 80

Ethanethiol (0.15 ml) was added dropwise to a stirred suspension ofsodium hydride (60% dispersion in mineral oil, 0.083 g) in DMPU (3 ml)which had been cooled to 3° C. and the mixture was stirred and allowedto warm to ambient temperature over 30 minutes. A solution of1-(6-methoxynaphth-2-ylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine(0.1 g) in DMPU (2 ml) was added and the mixture was stirred and heatedto 110° C. for 90 minutes. The mixture was cooled to ambient temperatureand partitioned between methylene chloride and water. The organic phasewas shaken with a slight excess of 2H aqueous sodium hydroxide. Theresultant precipitate was isolated and dried. There was thus obtained1-(6-hydroxynaphth-2-ylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinesodium salt (0.052 g);

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.5-1.73 (m, 4H), 2.72-3.23 (m, 7H),3.55 (t, 4H), 3.68-3.88 (m, 2H), 6.72 (m, 2H), 6.8 (m, 1H), 6.96 (m,1H), 7.45 (m, 2H), 7.69 (m, 1H), 7.99 (m, 1H), 8.11 (m, 2H);

Elemental Analysis Found C 53.8; H, 5.6; N, 10.0; C₂₅ H₂₇ N₄ O₄ S 3H₂ ONa requires C, 53.9; H, 5.9; N, 10.1%.

EXAMPLE 81

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with methyl2-[l-(² -naphthylsulphonyl)piperazin-2-yl]acetate to give2-methoxycarbonylmethyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 90% yield as a glass;

NMR Spectrum (CD₃ SOCD₃ +CD₃ CO₂ D, 100° C.) 1.6-1.85 (m, 4H), 2.4-2.65(m, 2H), 2.85-3.35 (m, 6H), 3.55 (s, 3H), 3.78 (m, 1H), 3.9-4.1 (m, 4H),4.45 (m, 1H), 6.95 (d, 2H), 7.68 (m, 2H), 7.8 (m, 1H), 7.95-8.15 (m,5H), 8.45 (d, 1H);

Elemental Analysis Found C, 61.7; H, 6.3; N, 10.3; C₂₈ H₃₂ N₄ O₅ S 0.5H₂O requires C, 61.65; H, 6.05; N, 10.3%.

The methyl 2-[1-(2-naphthylsulphonyl)piperazin-2-yl]acetate used as astarting material was obtained as follows:

Using an analogous procedure to that described in Example 2, methyl2-(1-benzylpiperazin-3-yl)acetate (J. Chem. Soc. Perkin I, 1992, 1035)was reacted with 2-naphthylsulphonyl chloride to give methyl2-[4-benzyl-1-(2-naphthylsulphonyl)piperazin-2-yl]acetate in 90% yield.

The material so obtained was reacted with 1-chloroethyl chloroformateusing an analogous procedure to that described in the second paragraphof the portion of Example 44 which is concerned with the preparation ofstarting materials. There was thus obtained methyl2-[1-(2-naphthylsulphonyl)piperazin-2-yl]acetate in 87% yield;

NMR Spectrum (CD 3SOCD₃) 2.55-2.7 (m, 2H), 2.9 (m, 1H), 3.05-3.45 (m,4H), 3.55 (s, 3H), 3.9 (m, 1H), 4.6 (m, 1H), 7.65-7.9 (m, 3H), 8.12 (m,3H), 8.55 (d, 1H), 9.3 (t, 2H).

EXAMPLE 82

Using an analogous procedure to that described in Example 1,1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with ethyl1-(6-bromonaphth-2-ylsulphonyl)piperazine-3-carboxylate to give4-(6-bromonaphth-2-ylsulphonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 42% yield, m.p. 117-121° C.;

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.2 (t, 3H), 1.5-1.8 (m, 4H), 2.55 (m,1H), 2.7-3.05 (m, 5H), 3.65-3.85 (m, 3H), 4.05-4.25 (m, 4H), 5.08 (m,1H), 6.7 (d, 2H), 7.77 (m, 2H), 8.1 (m, 4H), 8.3 (d, 1H), 8.45 (d, 1H).

Elemental Analysis Found C, 54.2; H, 5.2; N, 9.0; C₂₈ H₃₁ BrN₄ O₅ Srequires C, 54.6; H, 5.1; N, 9.1%.

The ethyl 1-(6-bromonaphth-2-ylsulphonyl)piperazine-3-carboxylate usedas a starting material was obtained in 71% yield from ethyl1-benzylpiperazine-2-carboxylate and 6-bromonaphth-2-ylsulphonylchloride using analogous procedures to those described in the portion ofExample 44 which is concerned with the preparation of startingmaterials.

EXAMPLE 83

Using an analogous procedure to that described in Example 61,4-(6-bromonaphth-2-ylsulphonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazinewas hydrolysed to give 4-(⁶-bromonaphth-2-ylsulphonyl)-2-carboxy-1-[l-(⁴-pyridyl)piperidin-4-ylcarbonyl]piperazine in 92% yield, m.p. 216-222°C. (decomposes);

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.5-1.8 (m, 4H), 2.52 (m, 1H), 2.7 (m,1H), 2.8-3.05 (m, 3H), 3.25 (m, 1H), 3.6-4.3 (m, 5H), 4.95 (m, 1H), 6.75(d, 2H), 7.75 (m, 2H), 8.0-8.15 (m, 4H), 8.3 (d, 1H), 8.4 (d, 1H).

Elemental Analysis Found C, 52.4; H, 4.8; N, 9.3; C₂₆ H₂₇ BrN₄ O₅ S0.5H₂ O requires C, 52.35; H, 4.7; N, 9.4%.

EXAMPLE 84

Using an analogous procedure to that described in Example 20,4-(6-bromonaphth-2-ylsulphonyl)-2-carboxy-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinewas reacted with morpholine to give4-(6-bromonaphth-2-ylsulphonyl)-2-morpholinocarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 60% yield, m.p. 235-237° C.;

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.5-1.8 (m, 4H), 2.7-3.05 (m, 5H), 3.4(m, 4H), 3.5-3.6 (m, 4H), 3.67 (m, 1H), 3.75-3.9 (m, 4H), 3.98 (m, 1H),5.2 (m, 1H), 6.65-6.8 (m, 2H), 7.75 (m, 2H), 8.1 (m, 4H), 8.3 (d, 1H),8.45 (d, 1H);

Elemental Analysis Found C, 53.7; H, 5.2; N, 10.2; C₃₀ H₃₄ BrN₅ O₅ S H₂O requires C, 53.5; H, 5.35; N, 10.4%.

EXAMPLE 85

A mixture of1-(6-chloronaphth-2-ylsulphonyl)-4-[1-(4,6-dichloro-1,3,5-triazin-2-yl)piperidin-4-ylcarbonyl]piperazine(0.891 g), magnesium oxide (0.5 g), 10% palladium-on-carbon catalyst(0.2 g) and DMF (15 ml) was stirred under an atmosphere of hydrogen gasuntil uptake of hydrogen ceased. The mixture was filtered and thefiltrate was partitioned between ethyl acetate and water. The organicphase was dried (MgSO₄) and evaporated. There was thus obtained 1-(²-naphthylsulphonyl)-4-[1-(1,3,5-triazin-2-yl)piperidin-4-ylcarbonyl]piperazine(0.36 g);

NMR Spectrum (CD₃ SOCD₃) 1.3-1.7 (m, 4H), 2.8-3.1 (m, 7H), 3.5-3.7(m.4H), 4.5-4.7 (m, 2H), 7.6-7.8 (m, 3H), 8.1-8.3 (m, 3H), 8.45 (s, 1H),8.55 (s, 2H).

EXAMPLE 86

Using an analogous procedure to that described in Example 56,2-amino-4-chloro-6-methylpyrimidine was reacted with1-(6-chloronaphth-2-ylsulphonyl)-4-(4-piperidinylcarbonyl)piperazine.The reaction mixture was concentrated by evaporation to one half of itsoriginal volume and cooled to ambient temperature. The precipitate whichformed was isolated, washed with diethyl ether and dried. There was thusobtained4-[1-(2-amino-6-methylpyrimidin-4-yl)piperidin-4-ylcarbonyl]-1-(6-chloronaphth-2-ylsulphonyl)piperazinein 39% yield, m.p. 210-212° C.;

NMR Spectrum (CD₃ SOCD₃) 1.2-1.6 (m, 4H), 2.0 (s, 3H), 2.8 (m, 3H),2.9-3.1 (m, 4H), 3.5-3.7 (m, 4H), 4.2 (m, 2H), 5.82 (s, 2H), 5.86 (s,1H), 7.7 (m, 1H), 7.8 (m, 1H), 8.2 (d, 1H), 8.25 (s, 1H), 8.3 (d, 1H),8.5 (s, 1H);

Elemental Analysis Found C, 56.3; H, 5.5; N, 15.3; C₂₅ H₂₉ ClN₆ O₃ S0.4H₂ O requires C, 55.9; H, 5.6; N, 15.7%.

EXAMPLE 87

Using an analogous procedure to that described in Example 56,4-chloropyrimidine was reacted with methyl4-(6-chloronaphth-2-ylsulphonyl)-1-(4-piperidinylcarbonyl)piperazine-2-carboxylateand the reaction product was purified by column chromatography usingincreasingly polar mixtures of methylene chloride and methanol to give4-(6-chloronaphth-2-ylsulphonyl)-2-methoxycarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 77% yield;

NMR Spectrum 1.6-2.0 (m, 4H), 2.5 (m, 2H), 2.8 (m, 1H), 3.0 (m, 1H),3.6-3.9 (m, 6H), 4.25-4.45 (m, 3H), 5.35 (m, 1H), 6.5 (d, 1H), 7.6 (m,1H), 7.75 (m, 1H), 7.95 (m, 3H), 8.2 (d, 1H), 8.35 (s, 1H), 8.6 (s, 1H);

Elemental Analysis Found C, 54.5; H, 5.2; N, 11.8; C₂₆ H₂₈ ClN₅ O₅ S0.2CH₂ Cl₂ requires C, 54.7; H, 4.9; N, 12.2%.

The methyl4-(6-chloronaphth-2-ylsulphonyl)-1-(4-piperidinylcarbonyl)piperazine-2-carboxylateused as a starting material was obtained as follows:

Benzyl chloroformate (8.5 g) was added dropwise to a stirred mixture ofethyl piperidine-4-carboxylate (7.85 g), triethylamine (6.95 ml) andmethylene chloride (50 ml) which had been cooled to 5° C. The mixturewas stirred at ambient temperature for 18 hours. The mixture waspartitioned between ethyl acetate and 2N aqueous hydrochloric acid. Theorganic phase was washed with water and with brine, dried (MgSO₄) andevaporated. The residue was dissolved in methanol (100 ml) and 2Naqueous sodium hydroxide (125 ml) was added. The mixture was stirred atambient temperature for 1 hour. The mixture was concentrated byevaporation and the residue was partitioned between diethyl ether andwater. The aqueous phase was acidified to pH 3 by the addition ofconcentrated hydrochloric acid and the mixture was extracted with ethylacetate. The organic extract was washed with water, dried (HgSO₄) andevaporated to give 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10.1g).

Oxalyl chloride (0.429 ml) and DMF (1 drop) were added to a stirredsolution of 1-benzyloxycarbonylpiperidine-4-carboxylic acid (0.622 g) inmethylene chloride (20 ml). The mixture was stirred at ambienttemperature for 2 hours and then evaporated. The residue was dissolvedin methylene chloride (10 ml) and added dropwise to a stirred mixture ofmethyl 4-(6-chloronaphth-2-ylsulphonyl)piperazine-3-carboxylate (0.93g), triethylamine (0.7 ml) and methylene chloride (10 ml) which had beencooled to 0° C. The mixture was stirred at ambient temperature for 2hours. The mixture was partitioned between ethyl acetate and 2N aqueoushydrochloric acid. The organic phase was washed with a saturated aqueoussodium bicarbonate solution, with water and with brine, dried (MgSO₄)and evaporated. The residue was purified by column chromatography usingincreasingly polar mixtures of hexane and ethyl acetate as eluent. Therewas thus obtained methyl1-(1-benzyloxycarbonylpiperidin-4-ylcarbonyl)-4-(6-chloronaphth-2-ylsulphonyl)piperazine-2-carboxylate(1.21 g);

NMR Spectrum 1.4-1.9 (m, 4H), 2.3-2.7 (m, 3H), 2.85 (m, 2H), 3.5-3.9 (m,6H), 4.15 (m, 2H), 4.35 (m, 1H), 5.1 (s, 2H), 5.3 (m, 1H), 7.2-7.4 (m,5H), 7.6 (m, 1H), 7.75 (m, 1H), 7.75-8.0 (m, 3H), 8.3 (s, 1H).

A mixture of a portion (0.512 g) of the material so obtained and asaturated solution of hydrogen bromide gas in glacial acetic acid (5 ml)was stirred at ambient temperature for 20 minutes. Diethyl ether (100ml) was added and the mixture was stirred vigorously. The precipitatewas isolated, washed with diethyl ether and dried. There was thusobtained methyl4-(6-chloronaphth-2-ylsulphonyl)-1-(4-piperidinylcarbonyl)piperazine-2-carboxylatewhich was used without further purification.

The methyl 4-(6-chloronaphth-2-ylsulphonyl)piperazine-3-carboxylate usedabove as an intermediate was obtained by the reaction of methyl1-benzylpiperazine-2-carboxylate (prepared in analogous fashion to thecorresponding ethyl ester which is described in Helv. Chim. Acta, 1962,45, 2383) and 6-chloronaphth-2-ylsulphonyl chloride using analogousprocedures to those described in the portion of Example 44 which isconcerned with the preparation of starting materials.

EXAMPLE 88

A mixture of4-(6-chloronaphth-2-ylsulphonyl)-2-methoxy-carbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine(0.362 g), 1N aqueous sodium hydroxide solution (1.3 ml) and methanol (5ml) was stirred and heated to reflux for 30 minutes. The mixture wasacidified by the addition of 2N aqueous hydrochloric acid (2 ml) andevaporated. The residue was dried to give2-carboxy-4-(6-chloronaphth-2-ylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine(0.41 g);

NMR Spectrum (CD₃ SOCD₃) 1.4-1.9 (m, 4H), 2.1-2.5 (m, 1H), 3.0-3.75 (m,8H), 4.0-4.3 (m, 2H), 5.12 (m, 1H), 7.2 (m, 1H), 7.7 (m, 1H), 7.85 (m,1H), 8.1-8.3 (m, 4H), 8.55 (s, 1H), 8.75 (s, 1H);

Elemental Analysis Found C, 41.0; H, 4.2; N, 9.4; C₂₅ H₂₆ ClN₅ O₅ S2NaCl 2H₂ O HCl requires C, 40.9; H, 4.3; N, 9.6%.

EXAMPLE 89

A solution of (E)-4-chlorostyrylsulphonyl chloride (0.12 g) in methylenechloride (2 ml) was added to a stirred suspension of4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]aniline (0.141 g) in methylenechloride (10 ml). The mixture was stirred at ambient temperature for 64hours. The resulting solid was isolated and washed with methylenechloride. The residue was purified by column chromatography using a 10:1mixture of methylene chloride and methanol as eluent. There was thusobtainedN-{4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]phenyl}-(E)-4-chlorostyrenesulphonamide(0.089 g), m.p. 207-209° C.;

NMR Spectrum (CD₃ SOCD₃, 100° C.) 3.43 (m, 4H), 3.6 (in, 4H), 6.8 (d,2H), 7.15 (d, 1H), 7.27 (d, 2H), 7.3-7.5 (m, 5H), 7.63 (d, 2H), 8.16 (d,2H);

Elemental Analysis Found C, 59.0; H, 4.9; N, 11.3; C₂₄ H₂₃ ClN₄ O₃ S0.25H₂ O requires C, 59.1; H, 4.9; N, 11.5%.

The 4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]aniline used as a startingmaterial was obtained as follows:

4-Nitrobenzoyl chloride (4.64 g) was added to a stirred suspension of1-(4-pyridyl)piperazine (4.08 g), triethylamine (3.48 ml) and DMF (50ml) which had been cooled to 4° C. The mixture was stirred at 4° C. for1 hour and at ambient temperature for 16 hours. The mixture waspartitioned between methylene chloride and water. The organic phase waswashed with brine, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography using a 10:1 mixture of methylenechloride and methanol as eluent. There was thus obtained4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]nitrobenzene (5.09 g), m.p.158-160° C.

A mixture of a portion (3.74 g) of the material so obtained, 10%palladium-on-carbon catalyst (0.3 g), 1N aqueous hydrochloric acid (24ml) and methanol (75 ml) was stirred under an atmosphere of hydrogen gasuntil uptake of hydrogen ceased. The mixture was filtered and thefiltrate was evaporated. The residue was dissolved in water (25 ml) andthe solution was basified to pH 10 by the addition of 1N aqueous sodiumhydroxide solution. The resultant precipitate was isolated, washed withwater and dried. There was thus obtained4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]aniline (2.91 g), m.p. 254-256°C.

EXAMPLE 90

Using an analogous procedure to that described in Example 89,4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]aniline was reacted with4'-bromo-4-biphenylylsulphonyl chloride to giveN-{4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]phenyl}-4'-bromo-4-biphenylylsulphonamidehydrochloride salt in 90% yield, m.p. 201-205° C.;

NMR Spectrum (CD₃ SOCD₃) 3.6 (m, 4H), 3.73 (m, 4H), 7.18 (m, 4H), 7.39(m, 2H), 7.69 (s, 4H), 7.9 (s, 4H), 8.27 (d, 2H);

Elemental Analysis Found C, 54.0; H, 4.4; N, 9.0; C₂₈ H₂₅ BrN₄ O₃ S HCl0.5H₂ O requires C, 54.0; H, 4.4; N, 9.0%.

EXAMPLE 91

Using an analogous procedure to that described in Example 20,4-(6-bromonaphth-2-ylsulphonyl)-2-carboxy-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinewas reacted with glycine methyl ester to give4-(6-bromonaphth-2-ylsulphonyl)-2-[N-(methoxycarbonylmethyl)carbamoyl]-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazinein 76% yield as a glass;

NMR Spectrum (CD₃ SOCD₃, 100° C.) 1.55-1.8 (m, 4H), 2.55-3.1 (m, 6H),3.4 (m, 1H), 3.65 (s, 3H), 3.7-3.95 (m, 4H), 4.15 (m, 2H), 4.95 (m, 1H),6.75 (d, 2H), 7.7-7.9 (m, 3H), 8.05-8.15 (m, 4H), 8.3 (d, 1H), 8.4 (d,1H);

Elemental Analysis Found C, 51.9; H, 5.0; N, 10.2; C₂₉ H₃₂ BrN₅ O₆0.75H₂ O requires C, 51.9; H, 5.0; N, 10.4%.

EXAMPLE 92

Using an analogous procedure to that disclosed in Example 2,1-(4-piperidinylcarbonyl)-4-(4-pyridyl)piperazine was reacted with6-bromonaphth-2-ylsulphonyl chloride to give1-[1-(6-bromonaphth-2-ylsulphonyl)piperidin-4-ylcarbonyl]-4-(4-pyridyl)piperazinein 20% yield, m.p. 229-230° C.;

NMR Spectrum (CD₃ SOCD₃) 1.6 (m, 4H), 2.3-2.7 (m, 3H), 3.5-3.8 (m, 10H),6.8 (d, 2H), 7.8 (d, 2H), 8.2 (t, 4H), 8.4 (d, 1H), 8.5 (d, 1H).

The 1-(4-piperidinylcarbonyl)-4-(4-pyridyl)piperazine used as a startingmaterial was obtained as follows:

Di-tert-butyl dicarbonate (5.09 g) was added to a stirred mixture ofpiperidine-4-carboxylic acid (3 g), sodium carbonate (2.48 g),1,4-dioxan (20 ml) and water (20 ml) which had been cooled to 0° C. Themixture was stirred at ambient temperature for 18 hours. The mixture wasconcentrated by evaporation to one third of the original volume and asaturated sodium bisulphate solution was added to bring the solution topH 2 to 3. The mixture was extracted with ethyl acetate. The organicphase was washed with water and with brine, dried (MgSO₄) and evaporatedto give 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (4.36 g) whichwas used without further purification.

Using an analogous procedure to that described in Example 14, a portion(1.41 g) of the material so obtained was reacted with1-(4-pyridyl)piperazine to give1-(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)-4-(4-pyridyl)piperazinein 20% yield;

NMR Spectrum (CD₃ SOCD₃) 1.4 (s, 9H), 1.6 (m, 2H), 2.9 (m, 6H), 3.4 (s,2H), 3.6 (d, 3H), 4.0 (m, 4H), 7.0-8.0 (m, 4H).

A mixture of the material so obtained (0.45 g), 4N aqueous hydrochloricacid (2 ml) and diethyl ether (15 ml) was stirred at ambient temperaturefor 18 hours. The mixture was evaporated to give 1-(⁴-piperidinylcarbonyl)-4-(4-pyridyl)piperazine (0.31 g) which was usedwithout further purification.

EXAMPLE 93

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically-acceptablesalt thereof (hereafter compound X), for therapeutic or prophylactic usein humans:

    ______________________________________                                        (a) Tablet I            mg/tablet                                                Compound X 100                                                                Lactose Ph. Eur 182.75                                                        Croscarmellose sodium  12.0                                                   Maize starch paste (5% w/v paste)  2.25                                       Magnesium stearate  3.0                                                      (b) Tablet II mg/tablet                                                        Compound X  50                                                                Lactose Ph. Eur 223.75                                                        Croscarmellose sodium  6.0                                                    Maize starch  15.0                                                            Polyvinylpyrrolidone (5% w/v paste)  2.25                                     Magnesium stearate  3.0                                                      (c) Tablet III mg/tablet                                                       Compound X  1.0                                                               Lactose Ph. Eur  93.25                                                        Croscarmellose sodium  4.0                                                    Maize starch paste (5% w/v paste)  0.75                                       Magnesium stearate  1.0                                                      (d) Capsule mg/capsule                                                         Compound X  10                                                                Lactose Ph. Eur 488.5                                                         Magnesium stearate  1.5                                                      (e) Injection I (50 mg/ml)                                                     Compound X  5.0% w/v                                                          1M Sodium hydroxide solution  15.0% v/v                                       0.1M Hydrochloric acid  4.5% w/v                                              (to adjust pH to 7.6)                                                         Polyethylene glycol 400  4.5% w/v                                             Water for injection to 100%                                                  (f) Injection II 10 mg/ml)                                                     Compound X  1.0% w/v                                                          Sodium phosphate BP  3.6% w/v                                                 0.1M Sodium hydroxide solution  15.0% v/v                                     Water for injection to 100%                                                  (g) Injection III (1 mg/ml, buffered to pH 6)                                  Compound X  0.1% w/v                                                          Sodium phosphate BP  2.26% w/v                                                Citric acid  0.38% w/v                                                        Polyethylene glycol 400  3.5% w/v                                             Water for injection to 100%                                                ______________________________________                                         Note                                                                          The above formulations may be obtained by conventional procedures well        known in the pharmaceutical art. The tablets (a)-(c) may be enteric coate     by conventional means, for example to provide a coating of cellulose          acetate phthalate.                                                       

CHEMICAL FORMULAE ##STR6##

What is claimed is:
 1. A compound of the formula I wherein:each of G¹and G³ is CH and G² is N, or each of G¹ and G² is CH and G³ is N; m is 1or 2; each R¹ is independently selected from hydrogen, amino, halogeno,cyano, (1-4C)alkyl and (1-4C)alkoxy; M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form a (1-4C)alkylene group, L¹ is(1-4C)alkylene, and T¹ is CH or N, and wherein 1 or 2 methylene groupswithin L¹ and the rings formed when R² and R³ are linked optionallybears a (1-4C)alkyl substituent; A is a direct link to the carbonylgroup, or A is (1-4C)alkylene; M² is a group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 0 or 1, T² is N, T³ is N, R⁴ is hydrogen or (1-4C)alkyl,R⁵ is hydrogen or (1-4C)alkyl, or R⁴ and R⁵ together form a(1-4C)alkylene, methylenecarbonyl or carbonylmethylene group, or R⁴ is a(2-3C)alkylene group which is linked to a methylene group within L²forming a 5- or 6-membered ring involving R⁴ and T², or R⁵ is a(2-3C)alkylene group which is linked to a methylene group within L²forming a 5- or 6-membered ring involving R⁵ and T³, L² is(1-4C)alkylene or (1-3C)alkylene-carbonyl, and, when r is 1, L² may alsobe carbonyl-(1 -3C)alkylene, and wherein 1 or 2 methylene groups withinL² and the rings formed when R⁴ and R⁵,R⁴ and L² or R⁵ and L² are linkedoptionally bears a substituent selected from the group consisting ofoxo, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin- 1 -ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl,N-(1-4C)alkyl-N-phenylcarbamoyl, N-[phenyl-(1-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]carbamoyl,N-[hydroxy-(2-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[hydroxy(2-3C)alkyl]carbamoyl,N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl,N-[carboxy-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[carboxy-(1-3C)alkyl]carbamoyl,N-[carboxy-(1-3C)alkyl]-N-[hydroxy-(2-3C)alkyl]carbamoyl,N-[carboxy-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl,N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl,N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[hydroxy-(2-3C)alkyl]carbamoyl,N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, (1-4C)alkyl, carboxy-(1-4C)alkyl,(1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl,N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl,pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl,morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl,N-phenylcarbamoyl-(1-4C)alkyl,N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl,(1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl,and wherein anyheterocyclic group in said substituent optionally bears 1 or 2substituents selected from the group consisting of (1-4C)alkyl,(1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl, and wherein anyphenyl or phenylene group in M² optionally bears 1 or 2 substituentsselected from the group consisting of halogeno, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy; M³ is a direct link to X, or M³ is a groupof the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 0 or 1, R⁶ is hydrogen or (1-4C)alkyl, or R⁵ and R⁶together form a (1-4C)alkylene, methylenecarbonyl or carbonylmethylenegroup, or R⁶ is a (2-3C)alkylene group which is linked to a methylenegroup within L³ forming a 5- or 6-membered ring involving NR⁶, L³ is(1-4C)alkylene or carbonyl-(1-3C)alkylene, and, when s is 1, L³ may alsobe (1-3C)alkylene-carbonyl, and wherein 1 or 2 methylene groups withinL³ and the rings formed when R⁵ and R⁶ or R⁶ and L³ are linkedoptionally bears a substituent selected from the group consisting ofoxo, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl,N-(1-4C)alkyl-N-phenylcarbamoyl, N-[phenyl-(1-3C)alkyl]carbamoyl,N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]carbamoyl, (1-4C)alkyl,carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl,carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl,N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl,pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl,morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl,N-phenylcarbamoyl-(1-4C)alkyl,N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl,(1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl, and wherein anyheterocyclic group in said substituent optionally bears 1 or 2substituents selected from the group consisting of (1-4C)alkyl,(1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl,N-(1-4C)alkylcarbamoyl and N,N-di-( 1-4C)alkylcarbamoyl, and wherein anyphenyl or phenylene group in M³ optionally bears 1 or 2 substituentsselected from the group consisting of halogeno, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy; X is oxy, thio, sulphinyl, sulphonyl,sulphonylamino, methylene, (1-4C)alkylmethylene ordi-(1-4C)alkylmethylene, or, when T³ is CH and M³ is a direct link to X,X may also be aminosulphonyl or oxycarbonyl; and Q is phenyl, naphthyl,phenyl-(1-4C)alkyl, phenyl-(2-4C)alkenyl, phenyl-(2-4C)alkynyl,(5-7C)cycloalkyl or a heterocyclic moiety containing up to 4 heteroatomsselected from the group consisting of nitrogen, oxygen and sulphur, andQ optionally bears 1, 2 or 3 substituents selected from the groupconsisting of hydroxy, amino, halogeno, cyano, trifluoromethyl, nitro,carboxy, carbamoyl, formyl, formimidoyl, formohydroximoyl,(1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, N-(1-4C)alkylcarbamoyl,N,N-di-(1-4C)alkylcarbamoyl, (1-4C)alkylamino, di-(1-4C)alkylamino,(2-4C)alkanoylamino, (2-4C)alkanoyl, (2-4C)alkanoimidoyl,(2-4C)alkanohydroximoyl, phenyl, heteroaryl, phenoxy, phenylthio,phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio,heteroarylsulphinyl, heteroarylsulphonyl, benzyl and benzoyl,and whereinsaid heteroaryl substituent or the heteroaryl group in aheteroaryl-containing substituent comprises a 5- or 6-memberedmonocyclic heteroaryl ring containing up to 3 heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulphur, and wherein saidphenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl,phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl,heteroarylsulphonyl, benzyl or benzoyl substituent optionally bears 1,2, 3 or 4 substituents selected from the group consisting of halogeno,trifluoromethyl, cyano, trifluoromethoxy, nitro, (1-4C)alkyl,(1-4C)alkoxy, hydroxy, amino, carboxy, carbamoyl, (1-4C)alkoxycarbonyl,N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, (1-4C)alkylamino,di-(1-4C)alkylamino, (2-4C)alkanoylamino and tetrazolyl; or apharmaceutically-acceptable salt thereof.
 2. A compound of the formula Ias claimed in claim 1 whereinm is 1 or 2; each R¹ is independentlyselected from hydrogen, amino, fluoro, chloro, bromo, cyano, methyl,ethyl and methoxy; M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group, L¹ is methylene orethylene, and T¹ is CH or N, and wherein 1 or 2 methylene groups withinL¹ and the ring formed when R² and R³ are linked optionally bears asubstituent selected from the group consisting of methyl and ethyl; A isa direct link to the carbonyl group or A is methylene; M² is a group ofthe formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 0 or 1, T² is N, T³ is N, R⁴ is hydrogen, methyl or ethyl,R⁵ is hydrogen, methyl or ethyl, or R⁴ and R⁵ together form a methylene,ethylene, trimethylene or methylenecarbonyl group, or R⁴ is an ethylenegroup which is linked to a methylene group within L² forming a 5- or6-membered ring involving R⁴ and T², and L² is methylene, ethylene,trimethylene or methylenecarbonyl, and wherein 1 or 2 methylene groupswithin L² and the ring formed when R⁴ and R⁵ are linked optionally bearsa substituent selected from the group consisting of oxo, carboxy,methoxycarbonyl, ethoxycarbonyl, carbamoyl, N-methylcarbamoyl,N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl,morpholinocarbonyl, piperazin-1-ylcarbonyl,4-methylpiperazin-1-ylcarbonyl, methyl, ethyl, carboxymethyl,methoxycarbonylmethyl, ethoxycarbonylmethyl, hydroxymethyl,methoxymethyl and benzyl, and wherein the pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl or4-methylpiperazin-1-ylcarbonyl substituent optionally bears a methyl orethyl substituent; M³ is a direct link to X, or M³ is a group of theformula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene orcarbonylethylene; X is thio, sulphinyl, sulphonyl, or methylene; and Qis phenyl, naphthyl, benzyl, phenethyl, styryl, 2-phenylethynyl,dibenzofuranyl, biphenylyl, pyridylphenyl or pyridylthienyl, and Qoptionally bears 1, 2 or 3 substituents selected from the groupconsisting of hydroxy, amino, fluoro, chloro, bromo, iodo, cyano,trifluoromethyl, nitro, carboxy, carbamoyl, methoxycarbonyl,ethoxycarbonyl, methyl, ethyl, methoxy and ethoxy; or apharmaceutically-acceptable salt thereof.
 3. A compound of the formula Ias claimed in claim 1 whereinm is 1 or 2; each R¹ is independentlyselected from hydrogen, amino, chloro, methyl and ethyl; M¹ is a groupof the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group, L¹ is ethylene, andT¹ is CH or N; A is a direct link to the carbonyl group or A ismethylene; M² is a group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 0 or 1, T² is N, T³ is N, R⁴ is hydrogen, R⁵ is hydrogen,or R⁴ and R⁵ together form an ethylene group, or R⁴ is an ethylene groupwhich is linked to a methylene group within L² forming a 5- or6-membered ring involving R⁴ and T², and L² is methylene or ethylene,and wherein 1 or 2 methylene groups within L² and the ring formed whenR⁴ and R⁵ are linked optionally bears a substituent selected from thegroup consisting of carboxy, methoxycarbonyl, ethoxycarbonyl,pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, methyl, ethyland benzyl,and wherein the pyrrolidin-1-ylcarbonyl, piperidinocarbonyl,morpholinocarbonyl, piperazin-1-ylcarbonyl or4-methylpiperazin-1-ylcarbonyl substituent optionally bears a methyl orethyl substituent; M³ is a direct link to X, or M³ is a group of theformula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene; X issulphonyl; and Q is phenyl, naphthyl, benzyl, phenethyl, styryl,2-phenylethynyl, dibenzofuranyl, biphenylyl, pyridylphenyl orpyridylthienyl, and Q optionally bears 1 or 2 substituents selected fromthe group consisting of fluoro, chloro, bromo, iodo, methyl, ethyl,methoxy and ethoxy; or a pharmaceutically-acceptable salt thereof.
 4. Acompound of the formula I as claimed in claim 1 whereineach of G¹ and G²is CH and G³ is N; m is 1; R¹ is hydrogen; M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group, L¹ is methylene orethylene, and T¹ is CH or N,and wherein 1 or 2 methylene groups withinL¹ and the ring formed when R² and R³ are linked optionally bears asubstituent selected from the group consisting of methyl and ethyl; A isa direct link to the carbonyl group or A is methylene; M² is a group ofthe formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is N, T³ is N, R⁴ is hydrogen, methyl or ethyl, R⁵is hydrogen, methyl or ethyl, or R⁴ and R⁵ together form a methylene,ethylene or trimethylene group, or R⁴ is an ethylene group which islinked to a methylene group within L² forming a 5- or 6-membered ringinvolving R⁴ and T², and L² is methylene, ethylene or trimethylene, andwherein 1 or 2 methylene groups within L² and the ring formed when R⁴and R⁵ are linked optionally bears a substituent selected from the groupconsisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl,N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl,andwherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituentoptionally bears one or two methyl or ethyl substituents; M³ is a directlink to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene orcarbonylethylene; X is sulphonyl; and Q is 3- or 4-biphenylyl whichoptionally bears, in the ring attached to X, 1 or 2 substituentsselected from the group consisting of hydroxy, fluoro, chloro, bromo,cyano, trifluoromethyl, methyl, ethyl, methoxy and ethoxy and whichoptionally bears in the terminal phenyl group up to 4 substituentsselected from the group consisting of fluoro, chloro, bromo,trifluoromethyl, cyano, trifluoromethoxy, methyl, ethyl, methoxy andethoxy; or a pharmaceutically-acceptable salt thereof.
 5. A compound ofthe formula I as claimed in claim 1 whereineach of G¹ and G² is CH andG³ is N; m is 1; R¹ is hydrogen; M¹ is a group of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group, L¹ is methylene orethylene, and T¹ is CH or N, and wherein 1 or 2 methylene groups withinL¹ and the ring formed when R² and R³ are linked optionally bears asubstituent selected from the group consisting of methyl and ethyl; A isa direct link to the carbonyl group or A is methylene; M² is a group ofthe formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is N, T³ is N, R⁴ is hydrogen, methyl or ethyl, R⁵is hydrogen, methyl or ethyl, or R⁴ and R⁵ together form a methylene,ethylene or trimethylene group, or R⁴ is an ethylene group which islinked to a methylene group within L² forming a 5- or 6-membered ringinvolving R⁴ and T², and L² is methylene, ethylene or trimethylene, andwherein 1 or 2 methylene groups within L² and the ring formed when R⁴and R⁵ are linked optionally bears a substituent selected from the groupconsisting of oxo, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl,N-methylcarbamoyl, N,N-dimethylcarbamoyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, methyl, ethyl and benzyl,andwherein the pyrrolidin-1-ylcarbonyl or piperidinocarbonyl substituentoptionally bears one or two methyl or ethyl substituents; M³ is a directlink to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene orcarbonylethylene; X is sulphonyl; and Q is benzyl, phenethyl, styryl or2-phenylethynyl which optionally bears 1, 2 or 3 substituents selectedfrom the group consisting of fluoro, chloro, bromo, cyano,trifluoromethyl, methyl, ethyl, methoxy and ethoxy; or apharmaceutically-acceptable salt thereof.
 6. A compound of the formula Ias claimed in any one of claims 1 to 5 wherein A is a direct link to thecarbonyl group.
 7. A compound of the formula I as claimed in claim 1wherein M² is a group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is N, T³ is N, R⁴ is hydrogen or (1-4C)alkyl, R⁵ ishydrogen or (1-4C)alkyl, or R⁴ and R⁵ together form a (1-4C)alkylenegroup and L² is (1-4C)alkylene.
 8. A compound of the formula I asclaimed in any one of claims 1 to 5 wherein M³ is a direct link to X. 9.A compound of the formula I as claimed in claim 1 or claim 2 wherein Xis sulphonyl.
 10. A compound of the formula I as claimed in claim 1 orclaim 7 wherein Q is phenyl, naphthyl or phenyl-(1-4C)alkyl whichoptionally bears 1, 2 or 3 substituents selected from the groupconsisting of hydroxy, halogeno, cyano, trifluoromethyl, (1-4C)alkyl,(1-4C)alkoxy, phenyl, phenoxy, phenylthio, phenylsulphinyl,phenylsulphonyl, benzyl and benzoyl, and wherein the phenyl group in aphenyl-containing substituent optionally bears 1 or 2 substituentsselected from the group consisting of halogeno, (1-4C)alkyl and(1-4C)alkoxy.
 11. A compound as claimed in claim 1 of the formula Ia##STR7## wherein G¹ is CH and G² is N; m is 1;R¹ is hydrogen; M¹ is agroup of the formula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which R² and R³ together form an ethylene group, L¹ is ethylene, andT¹ is CH or N; A is a direct link to the carbonyl group; M² is a groupof formula

    (T.sub.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which r is 1, T² is N, T³ is N, R⁴ is hydrogen, R⁵ is hydrogen, or R⁴and R⁵ together form an ethylene group, and L is ethylene, and wherein 1methylene group within L² optionally bears a substituent selected fromcarboxy, ethoxycarbonyl, N-methylcarbamoyl, piperidinocarbonyl, methyland benzyl; M³ is a direct link to X, or M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which s is 1, R⁶ is hydrogen and L³ is carbonylmethylene; X issulphonyl; and Q is 2-naphthyl which optionally bears 1 or 2substituents selected from the group consisting of fluoro, chloro,bromo, trifluoromethyl, methyl, methoxy and ethoxy; or apharmaceutically-acceptable acid-addition salt thereof.
 12. A compoundof the formula I as claimed in claim 1 selectedfrom1-[(E-4-chlorostyrylsulphonyl]-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]piperazine;1-(2-naphthylsulphonyl)-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]-piperazine; 1 -(6-chloronaphth-2-ylsulphonyl)-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl]piperazine; and4-[1-(2-aminopyrimidin-4-yl)piperidin-4-ylcarbonyl]-1-(6-chloronaphth-2-ylsulphonyl)piperazine;and pharmaceutically-acceptable salts thereof.
 13. A process for thepreparation of an aminoheterocyclic derivative of the formula I or ofthe formula Ia, or a pharmaceutically-acceptable salt thereof, asclaimed in claim 1 or claim 11 which comprises:(a) for the production ofthose compounds of the formula I or formula Ia wherein M² is a group ofthe formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which T² is N and r is 1, the reaction of an acid of the formula II,or a reactive derivative thereof, ##STR8## with an amine of the formula

    HNR.sup.4 -L.sup.2 -T.sup.3 R.sup.5 -M.sup.3 -X-Q;

(b) for the production of those compounds of the formula I or formula Iawherein M² is a group of the formula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which T³ is N, and wherein M³ is a direct link to X, the reaction ofan amine of formula III ##STR9## with a compound of the formula Z-X-Qwherein Z is a displaceable group; (c) for the production of thosecompounds of the formula I or formula Ia wherein M¹ is a group of theformula

    NR.sup.2 -L.sup.1 -T.sup.1 R.sup.3

in which T¹ is N, and wherein A is a direct link to the carbonyl group,the reaction of an amine of the formula IV ##STR10## with an acid of theformula

    HO.sub.2 C-M.sup.2 -M.sup.3 -X-Q

or a reactive derivative thereof; (d) for the production of thosecompounds of the formula I or formula Ia wherein M is a group of theformula

    (T.sup.2 R.sup.4).sub.r L.sup.2 -T.sup.3 R.sup.5

in which T³ is N, and wherein M³ is a group of the formula

    L.sup.3 -(NR.sup.6).sub.s

in which L³ is carbonylmethylene, the reaction of an amine of theformula III with an acid of the formula

    HO.sub.2 C-CH.sub.2 -(NR.sup.6).sub.s -X-Q

or a reactive derivative thereof; (e) for the production of thosecompounds of the formula I or formula Ia wherein M² is a group of theformula

    (T.sup.2 R.sup.4).sub.r -L.sup.2 -T.sup.3 R.sup.5

in which T³ is N, and wherein M³ is a direct link to X and X iscarbonylamino, the reaction of an amine of the formula III with anisocyanate of the formula

    OCN-X-Q;

(f) the reaction of a compound of the formula V ##STR11## wherein Z is adisplaceable group, with an amine of the formula

    HNR.sup.2 -L.sup.1 -T.sup.1 R.sup.3 -A-CO-M.sup.2 -M.sup.3 -X-Q

(g) for the production of those compounds of the formula I or formula Iawherein M², M³ or Q bears a carboxy or carboxy-containing group, thehydrolysis of a compound of the formula I wherein M², M³ or Q bears a(1-4C)alkoxycarbonyl group; (h) for the production of those compounds ofthe formula I or formula Ia wherein M², M³ or Q bears a carbamoyl,N-alkylcarbamoyl or N N-dialkylcarbamoyl group, the reaction of acompound of the formula I wherein M², M³ or Q bears a carboxy group, ora reactive derivative thereof, with ammonia or an appropriate alkylamineor dialkylamine; or (i) for the production of those compounds of theformula I or formula Ia wherein Q bears a hydroxy group, thedealkylation of a compound of the formula Ia wherein Q bears a(1-4C)alkoxy group; and optionally the reaction of the compound thusobtained with a suitable acid or base using a conventional procedure toform a pharmaceutically-acceptable salt of a compound of the formula Ia;and optionally carrying out one of the aforesaid procedures using anoptically active starting material, or carrying out a resolution of aracemic form of said compound using a conventional procedure, to obtainan optically active form of a compound of the formula I.
 14. Apharmaceutical composition which comprises a compound of the formula Ior of the formula Ia, or a pharmaceutically-acceptable salt thereof, asclaimed in claim 1 or claim 11, together with apharmaceutically-acceptable diluent or carrier.
 15. A method ofproducing an anticoagulant or antithrombotic effect in a warm bloodedanimal in need thereof, said method comprising administrating to saidanimal an anticoagulant or antithrombotic effective amount of a compoundaccording to claim
 1. 16. A method of producing a Factor Xa enzymeinhibitory effect in a warm blooded animal in need thereof, said methodcomprising administering to said animal a Factor Xa enzyme inhibitoryeffective amount of a compound according to claim
 1. 17. A method ofselectively producing a Factor Xa enzyme inhibitory effect in a warmblooded animal in need thereof, without inhibiting, or inhibiting to alesser extent, the enzyme thrombin, said method comprising administeringto said animal an amount of a compound according to claim 1 which iseffective to inhibit Factor Xa enzyme while having no, or a lesser,inhibitory effect on the enzyme thrombin.
 18. A method treating a FactorXa enzyme mediated disease or medical condition in a warm blooded animalin need of such treatment, said method comprising administering to saidanimal a Factor Xa enzyme inhibitory effective amount of a compoundaccording to claim
 1. 19. A method treating a thrombosis mediateddisease or medical condition in a warm blooded animal in need of suchtreatment, said method comprising administering to said animal anantithrombotic effective amount of a compound according to claim
 1. 20.A method treating a coagulation disorder in a warm blooded animal inneed of such treatment, said method comprising administering to saidanimal an anticoagulation effective amount of a compound according toclaim
 1. 21. A method treating a warm blooded animal having a thrombosisor embolism involving Factor Xa mediated coagulation, said methodcomprising administering to said animal an anticoagulation effectiveamount of a compound according to claim
 1. 22. A method of producing ananticoagulant effect ex vivo in a biological sample suspected to containFactor Xa enzyme, said method comprising introducing into saidbiological sample an anticoagulant-effective amount of a compoundaccording to claim
 1. 23. The method of claim 22 wherein said biologicalsample is whole blood.